Kasabach-Merritt Syndrome

MONDO:0007708 Pathograph 12 Show in embeddings browser blood coagulation disease vascular neoplasm

A life-threatening consumptive coagulopathy that arises inside a vascular tumour and nowhere else. Profound thrombocytopenia, hypofibrinogenemia and a rising D-dimer appear in an infant with an enlarging purpuric mass, and the platelets are not being destroyed in the circulation but trapped and consumed within the lesion itself. The tumour is kaposiform hemangioendothelioma, or less often tufted angioma, and the two are regarded as one neoplastic spectrum. Ordinary infantile hemangioma does not do this. The modern literature prefers "Kasabach-Merritt phenomenon" precisely because the entity is a complication of a specific tumour rather than an independent inherited syndrome; the name kept here is the MONDO label. The initiating lesion of the tumour is unknown in most cases, so this pathograph begins at the abnormal vascular bed and follows the platelet.

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7
Pathophys.
2
Histopath.
8
Phenotypes
12
Pathograph
1
Genes
5
Medical Actions
2
Differentials
5
Trials
11
References
1
Deep Research
⚙

Pathophysiology

7
Abnormal Angiogenic and Lymphangiogenic Tumour Vasculature
The lesion is built of infiltrating nodules of spindled endothelial cells forming slit-like blood channels and malformed lymphatic channels. Abnormal angiogenesis and lymphangiogenesis are its defining pathological features. What starts the process is not known, and the review that is the main source for this entry says so plainly. A somatic activating GNA14 variant is found in a minority of specimens and is not required.
endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology. lymphatic endothelial cell CL:0002138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves lymphatic endothelial cell, annotated with endothelial cell of lymphatic vessel (CL:0002138). CL:0002138 is a cell type from the Cell Ontology.
angiogenesis GO:0001525 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased angiogenesis (GO:0001525). GO:0001525 is a biological process from the Gene Ontology. ↑ INCREASED lymphangiogenesis GO:0001946 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased lymphangiogenesis (GO:0001946). GO:0001946 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Intralesional Platelet Trapping and Activation The abnormal channels trap platelets. Podoplanin on the lesional endothelium and CLEC-2 on the platelet are the best characterised route, with exposed matrix a second proposed one.
Show evidence (2 references)
PMID:32014025 SUPPORT Human Clinical
"The main pathological features of KHE are abnormal angiogenesis and lymphangiogenesis."
States the two processes that define the lesion this node describes.
PMID:32014025 SUPPORT Human Clinical
"The initiating mechanism during the pathogenesis of KHE has yet to be discovered."
Records the honest state of knowledge upstream of this node, which is why the pathograph starts here rather than at a genetic lesion.
Podoplanin-CLEC-2 Platelet Adhesion Signalling
Podoplanin is widely expressed on the endothelium inside the lesion. It binds platelet CLEC-2, and the signal runs through Src family kinases to activate the platelet. The pathway is credible and incomplete: podoplanin is also highly expressed in lymphatic malformations, and those lesions do not aggregate platelets. Something further about the architecture or the flow is required.
platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology.
platelet activation GO:0030168 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased platelet activation (GO:0030168). GO:0030168 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Intralesional Platelet Trapping and Activation Receptor engagement is the proximal activating signal for the trapped platelet.
Show evidence (3 references)
PMID:32014025 SUPPORT Human Clinical
"Binding of podoplanin to CLEC-2 can transmit platelet activation signals via Src family kinases, which may account for platelet aggregation in KHE"
States the signalling route this node asserts, and its own hedge.
PMID:32014025 SUPPORT Human Clinical
"Podoplanin is highly expressed in dysmorphic vessels within the lymphatic malformations, but no obvious platelet aggregation occurs in these lesions"
The negative comparison that keeps this node from being written as sufficient. Podoplanin expression alone does not produce the phenomenon.
PMID:37307200 SUPPORT Human Clinical
"In KHE/KMP, platelet responses induced by CLEC-2 or GPVI activation are impaired because of the diminished number of receptors on the platelet surface. This impairment correlates with the severity of the disease and resolves as the patient recovers."
Measures the receptor on circulating platelets in patients and finds it depleted in proportion to disease severity, recovering with treatment. That is what chronic engagement of CLEC-2 inside the lesion would be expected to do, and it ties this node to the clinical course.
Intralesional Platelet Trapping and Activation
Platelets are held inside the tumour vasculature, activated, and aggregated. This is the pivot of the whole disease. Trapping alone is not the disease: it is seen histologically in lesions that never develop the coagulopathy, so it is necessary and not sufficient.
platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology.
platelet aggregation GO:0070527 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased platelet aggregation (GO:0070527). GO:0070527 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Shear-Driven Amplification Loop Microvascular thrombi obstruct flow, and the disturbed flow activates more platelets.
Consumptive Coagulopathy Aggregation activates the coagulation cascade and consumes clotting factors.
Show evidence (2 references)
PMID:32014025 SUPPORT Human Clinical
"Intralesional platelet trapping is followed by the activation and aggregation of platelets, which then results in activation of the coagulation cascade with subsequent consumption of clotting factors."
States the node and the step that follows it.
PMID:32014025 SUPPORT Human Clinical
"Platelet trapping has been revealed histologically in KHE with or without KMP"
Establishes that trapping occurs in tumours that never produce the coagulopathy, which is why this node is described as necessary rather than sufficient.
Shear-Driven Amplification Loop
Thrombi obstruct the small convoluted vessels of the lesion, flow becomes turbulent, shear rises, and high shear activates further platelets through von Willebrand factor and its platelet binding sites. The disease feeds itself, and this is why the active phase escalates over days.
platelet activation GO:0030168 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased platelet activation (GO:0030168). GO:0030168 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Intralesional Platelet Trapping and Activation The returning arm of the loop. High shear drives further trapping and activation, which is what makes the active phase self-amplifying.
Show evidence (1 reference)
PMID:32014025 SUPPORT Human Clinical
"With regard to KHE, platelets in circulating blood may become exposed to turbulent blood flow and high shear stress that results from the architecture of the small, convoluted and thrombus-obstructed vessels within the KHE lesions. This process in turn causes further platelet trapping and..."
States the loop, including that it drives further trapping, which is the claim of this node.
Consumptive Coagulopathy
Profound thrombocytopenia, falling fibrinogen and a rising D-dimer, produced by consumption rather than by marrow failure or immune destruction. Unlike disseminated intravascular coagulation, the driving consumption is localised to the tumour.
blood coagulation GO:0007596 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased blood coagulation (GO:0007596). GO:0007596 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Intralesional Haemorrhage and Tumour Engorgement Continued aggregation with hypofibrinogenemia and raised D-dimer ends in bleeding into the lesion, which is what makes the mass purpuric, warm, painful and rapidly larger.
Show evidence (1 reference)
PMID:38903724 SUPPORT Human Clinical
"KHE may develop into the Kasabach-Merritt phenomenon (KMP), which is characterized by thrombocytopenia and consumptive coagulopathy."
Defines the node in the terms used here.
Intralesional Haemorrhage and Tumour Engorgement
Bleeding into the tumour. The mass turns deep purple, becomes hot and tender, and enlarges over days. Anaemia follows from sequestration, from bleeding and from microangiopathic destruction of red cells in the abnormal vessels.
Downstream
Local Infiltrative Tissue Destruction Expansion during the active phase adds to the infiltrative damage the tumour is already doing to muscle, joint and bone.
Show evidence (1 reference)
PMID:32014025 SUPPORT Human Clinical
"Continued platelet aggregation, together with coagulopathy and hypofibrinogenemia with elevated D-dimer (coagulation markers), eventually result in intralesional hemorrhage, which clinically manifests as very purpuric, warm, painful, and rapidly enlarged tumor lesion"
Describes this node and its clinical appearance.
Local Infiltrative Tissue Destruction
The tumour infiltrates rather than displaces. Muscle and connective tissue are remodelled, joints are eroded, bone is destroyed, and the survivors of the acute coagulopathy are left with contracture, scoliosis, chronic pain and lymphedema. This arm runs in tumours that never develop the coagulopathy at all.
Show evidence (2 references)
PMID:32014025 SUPPORT Human Clinical
"In some cases, residual KHEs will continue to infiltrate surrounding tissues, erode bone and destroy joints."
States the tissue destruction this node describes.
PMID:32014025 SUPPORT Human Clinical
"Even in patients without KMP, musculoskeletal disorders are frequently seen in cases involving the extremities, with a majority of these lesions located on or adjacent to joints"
Establishes that this arm is not downstream of the coagulopathy alone, which is why it is drawn as a separate consequence of the lesion.
✶

Histopathology

2
Infiltrating nodules of spindle endothelial cells
The architectural hallmark. The nodules are infiltrative rather than encapsulated, which is the histological form of the invasive growth the first pathophysiology node describes.
Show evidence (1 reference)
PMID:32014025 SUPPORT Human Clinical
"The histologic hallmark of KHE is infiltrating, defined, rounded and confluent nodules, which are composed of spindle endothelial cells."
States the hallmark and its cellular composition.
Slit-like channels with platelet thrombi and hemosiderin
The microscopic counterpart of the trapping node: platelet thrombi are visible inside the lesion, and the hemosiderin records bleeding that has already occurred there.
Show evidence (1 reference)
PMID:32014025 SUPPORT Human Clinical
"These spindle endothelial cells align to form malformed lymphatic channels and slit-like vascular lumina containing erythrocytes, along with platelet thrombi, eosinophilic hyaline bodies and the extravasation of hemosiderin deposits."
Names the platelet thrombi and hemosiderin within the malformed channels, which is the histological evidence for intralesional trapping and haemorrhage.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Kasabach-Merritt Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

8
Blood 5
Profound Thrombocytopenia VERY_FREQUENT HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38903724 SUPPORT Human Clinical
"The median platelet count of patients who were associated with KMP was 24,000/µL in our cohort."
Gives the platelet count in the cohort, supporting both the phenotype and its severity.
PMID:38903724 SUPPORT Human Clinical
"Common clinical characteristics included associated coagulation disorder (100%), locally aggressive cutaneous blue-purple mass (89%), thrombocytopenia (78%), and local pain or joint dysfunction (20%)."
Gives the 78% figure in the cohort, which is the basis for the VERY_FREQUENT band as applied to the tumour population this entry describes.
Hypofibrinogenemia HP:0011900 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypofibrinogenemia (HP:0011900). HP:0011900 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32014025 SUPPORT Human Clinical
"Currently, KMP is defined as profound thrombocytopenia, together with consumptive coagulopathy and hypofibrinogenemia associated only with the vascular tumors, KHE and tufted angioma"
Places hypofibrinogenemia in the definition of the entity.
Microangiopathic Hemolytic Anemia HP:0001937 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microangiopathic hemolytic anemia (HP:0001937). HP:0001937 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34106442 SUPPORT Human Clinical
"The child was moribund with microangiopathic hemolytic anemia, thrombocytopenia, and consumptive coagulopathy without sepsis."
Documents the finding alongside the thrombocytopenia and coagulopathy in a case of this disease.
Bruising and Bleeding Bruising susceptibility HP:0000978 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bruising susceptibility (HP:0000978). HP:0000978 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32014025 SUPPORT Human Clinical
"KHE lesions with KMP have progressive engorgement and purpura. KMP can lead to significant pain and secondary bleeding."
Names purpura and secondary bleeding as features of the phenomenon, which is what this phenotype records.
Anemia VERY_FREQUENT HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38903724 SUPPORT Human Clinical
"Almost all patients with KHE have different degrees of anemia at the time platelet level was dropping"
Ties anemia to the period of platelet decline and puts its frequency at almost all patients.
Cardiovascular 1
Locally Aggressive Blue-Purple Cutaneous Mass VERY_FREQUENT Vascular neoplasm HP:0100742 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vascular neoplasm (HP:0100742). HP:0100742 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38903724 SUPPORT Human Clinical
"Common clinical characteristics included associated coagulation disorder (100%), locally aggressive cutaneous blue-purple mass (89%), thrombocytopenia (78%), and local pain or joint dysfunction (20%)."
Gives the lesion description and its 89% frequency in the cohort, which supports the VERY_FREQUENT band.
Metabolism 1
Lymphedema HP:0001004 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphedema (HP:0001004). HP:0001004 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32014025 SUPPORT Human Clinical
"In this scenario, it is hypothesized that the mechanical obstruction of the lymphatic flow during the acute phase of KMP may eventually lead to lymphedema"
States the phenotype and, as a hypothesis, its proposed mechanism. The hedge is the source's own.
Musculoskeletal 1
Pain and Joint Dysfunction OCCASIONAL Limitation of joint mobility HP:0001376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Limitation of joint mobility (HP:0001376). HP:0001376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38903724 SUPPORT Human Clinical
"Common clinical characteristics included associated coagulation disorder (100%), locally aggressive cutaneous blue-purple mass (89%), thrombocytopenia (78%), and local pain or joint dysfunction (20%)."
Gives the 20% figure that supports both the phenotype and the OCCASIONAL band.
🧬

Genetic Associations

1
GNA14
Gene: GNA14 hgnc:4382 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GNA14 (hgnc:4382). hgnc:4382 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER
Show evidence (2 references)
PMID:32014025 SUPPORT Human Clinical
"mutation was found in 1/3 of KHE specimens and in 1/4 of TA specimens, although these studies were weakened by small sample size"
Gives the frequency of the variant and the source's own caveat about sample size.
PMID:31887709 REFUTE Human Clinical
"Using next generation sequencing, heterogeneous mutations were found in a subset of cases (2/7) without the presence of GNA14 mutations, previously reported in KHE and TA."
A negative series. Tagged REFUTE against any reading of the variant as a constant feature of the tumour, which is why the notes above call it neither necessary nor sufficient.
💊

Medical Actions

5
Sirolimus
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sirolimus CHEBI:9168 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sirolimus (CHEBI:9168). CHEBI:9168 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
An mTOR inhibitor, and the drug that changed the outlook for this disease. It acts on the tumour rather than on the platelet, which is the right place: the coagulopathy stops when the lesion stops. A prospective multicentre phase II trial in 126 children with complicated vascular anomalies found 77.8% objective response, with rates above 80% in the kaposiform hemangioendothelioma subgroup. Serious adverse events occurred, including grade 4 pneumonitis, and two patients in a separate surgical cohort stopped the drug for severe pneumonia.
Mechanism Target:
INHIBITS Abnormal Angiogenic and Lymphangiogenic Tumour Vasculature — mTOR sits downstream of the VEGF-C/VEGFR-3 and Ang-2/Tie-2 signalling that drives the lesion's lymphangiogenesis, so inhibiting it acts on the abnormal vascular bed itself.
Show evidence (1 reference)
PMID:32014025 SUPPORT Human Clinical
"The binding of VEGF-C can stimulate the activation of VEGFR-3 and induce downstream PI3K/Akt/mTOR signaling, which mediates lymphangiogenesis."
Places mTOR in the pathway that produces the abnormal vasculature, which is why the drug is drawn as inhibiting this node.
Show evidence (2 references)
PMID:34082006 SUPPORT Human Clinical
"Of 126 patients enrolled on an intention-to-treat basis, 98 (77.8%) had had an objective response to sirolimus, with a ≥20% decrease in lesion volume."
The prospective trial result behind this treatment.
PMID:34082006 SUPPORT Human Clinical
"More serious adverse events included reversible grade 4 pneumonitis in 3 patients and grade 4 upper respiratory infection in 1 patient."
Records the toxicity of the drug from the same trial, which is what makes the pneumonia deaths reported elsewhere credible rather than incidental.
Corticosteroid Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: prednisolone CHEBI:8378 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses prednisolone (CHEBI:8378). CHEBI:8378 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
High-dose corticosteroid, commonly methylprednisolone 5 to 6 mg/kg daily, used first or alongside sirolimus. Response is partial and unreliable: 36% of 55 patients with the coagulopathy in one cohort were steroid-sensitive. That is why it is not used alone in severe disease.
Mechanism Target:
MODULATES Consumptive Coagulopathy — Steroid is given to bring the platelet count up in the acute phase. The mechanism by which it does so in this disease is not established, and the response rate is low, so the edge is graded as modulating rather than inhibiting.
Show evidence (1 reference)
PMID:38903724 SUPPORT Human Clinical
"In 55 patients with KMP, 36% were sensitive to high-dose corticosteroid therapy."
Gives the response rate in patients with the coagulopathy, which is the claim this edge makes and the reason it is not graded as inhibition.
Show evidence (1 reference)
PMID:38903724 SUPPORT Human Clinical
"Ninety-two percent of patients were given surgery treatment and 89% of these patients were given high-dose methylprednisolone (5-6 mg/kg daily) before surgery."
Documents the agent, the dose and its use before surgery in this cohort.
Vincristine
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: vincristine CHEBI:28445 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses vincristine (CHEBI:28445). CHEBI:28445 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
A vinca alkaloid, long recommended with corticosteroid by the 2013 consensus statement and still used where sirolimus fails or is not tolerated. The recommendation rests on expert opinion, not on trials, and the review that reports it says so. That gap is not for want of trying: NCT02110069 was a randomised head-to-head comparison of vincristine against sirolimus and terminated with four participants enrolled, so the comparison this recommendation needs was attempted and could not accrue.
Mechanism Target:
INHIBITS Abnormal Angiogenic and Lymphangiogenic Tumour Vasculature — Cytotoxic action against the proliferating tumour.
Show evidence (1 reference)
PMID:32014025 SUPPORT Human Clinical
"Medical treatments with corticosteroids and/or vincristine have been recommended for the management of KHE."
Establishes the drug's place in management of the tumour, which is the node this edge points at.
Show evidence (1 reference)
PMID:32014025 SUPPORT Human Clinical
"However, these recommendations are based on expert opinion rather than rigorous clinical studies."
The source's own grading of the evidence behind the corticosteroid and vincristine recommendations. Recorded here so the entry does not overstate them.
Surgical Resection
Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Platform: Surgery
Complete resection can cure a localised lesion. In one cohort all eight low-risk patients who were operated on recovered without recurrence over up to five years of follow-up. Active severe coagulopathy makes surgery hazardous, so it is usually preceded by medical control.
Mechanism Target:
INHIBITS Abnormal Angiogenic and Lymphangiogenic Tumour Vasculature — Removes the vascular bed in which platelets are trapped.
Show evidence (1 reference)
PMID:38903724 SUPPORT Human Clinical
"Patients from the low-risk group (eight cases) underwent operation, all of whom recovered without recurrence after a maximum follow-up of 5 years."
Removing the lesion resolved the disease in this group, which is what this edge asserts.
Show evidence (1 reference)
PMID:38903724 SUPPORT Human Clinical
"Our study describes the largest assessment of high-risk patients with KHE who have undergone an operation to date, with 5 years of follow-up to track recovery"
Establishes the surgical cohort this treatment entry draws on.
Supportive Transfusion Management
Action: supportive transfusion managementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive transfusion management, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
The management point that follows directly from the trapping node. Transfused platelets are consumed by the lesion like endogenous ones, so transfusing them does not durably raise the count and is restricted to active bleeding or an imminent procedure. Red cells and plasma products are the supportive measures that do help, correcting anemia and the coagulopathy respectively.
Mechanism Target:
MODULATES Consumptive Coagulopathy — Plasma products replace what the lesion consumes. This corrects the laboratory abnormality without acting on the tumour that causes it, which is why the effect is MODULATES and not INHIBITS.
Show evidence (1 reference)
PMID:38903724 SUPPORT Human Clinical
"infusion of suspended red blood cells and fresh frozen plasma with cold precipitation to correct anemia and improve coagulation"
Names the blood products used and what each corrects, which is the claim this edge makes.
Show evidence (2 references)
PMID:32014025 SUPPORT Human Clinical
"Platelet transfusion should not be used unless the patient is actively bleeding or in preparation for surgery."
The restriction itself, with the two exceptions that permit platelet transfusion.
PMID:38903724 SUPPORT Human Clinical
"Platelet transfusion alone was not effective for KMP cases as platelet counts dropped rapidly to previous levels within 48 h."
The observation behind the restriction: transfused platelets are consumed within 48 hours, so the transfusion does not hold.
🔬

Diagnosis

3
Platelet count, fibrinogen and D-dimer
The laboratory triad. Serial measurement is how the active phase is followed and how response to treatment is judged.
Show evidence (2 references)
PMID:32014025 SUPPORT Human Clinical
"Currently, KMP is defined as profound thrombocytopenia, together with consumptive coagulopathy and hypofibrinogenemia associated only with the vascular tumors, KHE and tufted angioma"
Gives the platelet count and fibrinogen limbs of this assessment as the defining laboratory findings.
PMID:32014025 SUPPORT Human Clinical
"Continued platelet aggregation, together with coagulopathy and hypofibrinogenemia with elevated D-dimer (coagulation markers), eventually result in intralesional hemorrhage, which clinically manifests as very purpuric, warm, painful, and rapidly enlarged tumor lesion"
Names the D-dimer limb and calls these coagulation markers, which is the third measurement in this assessment.
Doppler ultrasound and contrast-enhanced MRI
Imaging establishes the extent of the lesion, which physical examination understates because the tumour infiltrates. Ultrasound serves superficial lesions; contrast MRI is the modality that maps deep involvement and is what makes a lesion visible when there is no cutaneous component to see. This is the assessment the cutaneous-mass phenotype refers to when it says unexplained neonatal thrombocytopenia warrants imaging of the chest and abdomen.
Show evidence (3 references)
PMID:32014025 SUPPORT Human Clinical
"Ultrasound is the modality of choice for small and superficial lesions"
Gives ultrasound its scope: the superficial lesion, not the deep one.
PMID:32014025 SUPPORT Human Clinical
"MRI with and without gadolinium has the most value in the diagnosis of KHE as well as for clearly determining the extent of involvement and response to treatment"
States why MRI carries the diagnostic weight here, and that it is also what tracks treatment response.
PMID:32014025 SUPPORT Human Clinical
"MRI scan of the abdomen and chest should be recommended for such patients"
The source recommendation behind the chest and abdominal imaging that this entry asserts in the cutaneous-mass phenotype description.
Lesional biopsy with immunohistochemistry
The reference standard, and the assessment that settles the differential against infantile hemangioma by GLUT1 staining. It is qualified rather than recommended outright: biopsy can worsen a severe coagulopathy, which is why the diagnosis is often made on clinical and imaging grounds instead.
Show evidence (3 references)
PMID:32014025 SUPPORT Human Clinical
"Biopsy is gold standard for diagnosis and should be performed if possible and safe."
Establishes biopsy as the reference standard, with the safety condition attached in the same sentence.
PMID:32014025 SUPPORT Human Clinical
"Biopsy is frequently not possible or recommended in KHE with severe KMP, and can potentially worsen the coagulopathy."
The reason this assessment is often deferred. Recorded so the entry does not present biopsy as routinely available in severe disease.
PMID:32014025 SUPPORT Human Clinical
"Immunohistochemical staining shows that endothelial cells in KHE lesions are positive both for vascular endothelial markers CD31 and CD34, lymphatic endothelial marker VEGFR-3, D2–40, lymphatic endothelial hyaluronan receptor-1 and Prox-1, but negative for glucose transporter-1(Glut-1) and human..."
The immunophenotype. The GLUT1-negative limb is the discriminator that differential_diagnoses already uses against infantile hemangioma.
📈

Progression

3
Lesion present at or soon after birth
Age: Birth to first year
The tumour is congenital or near-congenital in most cases. The coagulopathy is not present from the outset; it develops within the lesion afterwards.
Show evidence (2 references)
PMID:32014025 SUPPORT Human Clinical
"Approximately 50% of cutaneous lesions are visible or detectable at birth"
Puts half of cutaneous lesions at birth, establishing this as the starting phase.
PMID:32014025 SUPPORT Human Clinical
"The distribution of age at onset has one peak within the first year of life when approximately 90% of KHE are evident."
Bounds the onset window for the tumour as a whole.
Active Kasabach-Merritt phase
Age: First days to months of life
The phase the pathograph models. The lesion enlarges and becomes engorged and purpuric as platelets are trapped, which is the visible correlate of the trapping and haemorrhage nodes rather than growth of tumour bulk.
Show evidence (1 reference)
PMID:32014025 SUPPORT Human Clinical
"KHE tumors that develop KMP will appear to ‘grow’ and become engorged and purpuric in the first days/weeks/months of life"
Describes the enlargement and purpuric change as the presentation of the phenomenon, and places it in the first days to months.
Chronic residual phase
Survival of the acute phase does not end the disease. Residual tumour continues to infiltrate, and fibrosis is the pathological end state, which is what links the infiltrative-destruction arm of the pathograph to the lasting musculoskeletal and lymphatic morbidity.
Show evidence (3 references)
PMID:32014025 SUPPORT Human Clinical
"In some cases, residual KHEs will continue to infiltrate surrounding tissues, erode bone and destroy joints."
States that residual lesions keep infiltrating and destroying bone and joint after the acute phase.
PMID:32014025 SUPPORT Human Clinical
"Pathologically, untreated KHE lesions are characterized by progressive fibrosis"
Names fibrosis as the pathological end state of untreated lesions.
PMID:32014025 SUPPORT Human Clinical
"Lymphedema may be a potential sequela of KHE, particularly tumor involving the legs"
Records lymphedema as a chronic sequela, matching the phenotype already curated.
📊

Prevalence

2
Children, Massachusetts
Annual Incidence 0.071 per 100,000 <1 in 1,000,000 per year
Incidence of the underlying tumour, kaposiform hemangioendothelioma, not of the coagulopathy. The source states that the true figure is probably higher because small asymptomatic lesions go unreported.
Show evidence (1 reference)
PMID:32014025 SUPPORT Human Clinical
"In Massachusetts, the annual prevalence and incidence have been estimated at 0.91 and 0.071 per 100,000 children, respectively"
Gives the incidence figure and the population it was measured in.
Children with kaposiform hemangioendothelioma, single Chinese centre, 2017-2022
Period Prevalence >1 in 1,000
The fraction of the underlying tumour that goes on to the coagulopathy. This is a surgical referral cohort of 70 patients, so it sits at the high end; reviews give a wider range across series.
Show evidence (1 reference)
PMID:38903724 SUPPORT Human Clinical
"Of the total cohort, 78% developed KMP; the median age at which thrombocytopenia occurred was 27.8 days."
Gives the proportion of the tumour cohort developing the coagulopathy and the age at which it declares itself.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Kasabach-Merritt Syndrome:

Infantile hemangioma
Overlapping Features The commonest misdiagnosis and the most consequential. Infantile hemangioma is GLUT1-positive and does not produce the coagulopathy. Historic reports attributing Kasabach-Merritt to it were wrong.
Distinguishing Features
  • GLUT1 positive on immunohistochemistry
  • Does not cause consumptive coagulopathy
Show evidence (1 reference)
PMID:32014025 SUPPORT Human Clinical
"Currently, KMP is defined as profound thrombocytopenia, together with consumptive coagulopathy and hypofibrinogenemia associated only with the vascular tumors, KHE and tufted angioma"
The word "only" is the discriminating claim. The phenomenon belongs to these two tumours and not to infantile hemangioma.
Kaposiform lymphangiomatosis
Overlapping Features Multifocal thoracic and osseous lymphatic disease. It carries a somatic NRAS p.Q61R variant that is absent from kaposiform hemangioendothelioma, which gives a molecular means of separating them, and it does worse.
Distinguishing Features
  • Somatic NRAS p.Q61R present
  • Multifocal thoracic and osseous involvement
Show evidence (1 reference)
PMID:32014025 SUPPORT Human Clinical
"variant (c.182 A > G, p. Q61R) was recently identified in patients with KLA but was absent in KHE samples, thus providing a molecular means to further differentiate these two entities"
States the molecular discriminator between the two entities.
🔬

Clinical Trials

5
NCT03188068 PHASE_II COMPLETED
The only registered trial scoped to the coagulopathy rather than to the tumour alone: sirolimus against sirolimus plus prednisolone in kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon. Completed with 30 participants.
Target Phenotypes: Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT03188068 SUPPORT Human Clinical
"The purpose of this study is to compare the efficacy and safety of orally administered sirolimus versus sirolimus plus pednisolone in the treatment of KHE associated with KMP."
States the comparison and, unusually among these trials, scopes it to KHE associated with KMP rather than to the tumour generally.
NCT02110069 PHASE_II TERMINATED
The head-to-head vincristine against sirolimus comparison. It terminated with four participants enrolled, which is the concrete reason the vincristine recommendation still rests on expert opinion: the trial that would have settled it could not accrue in a disease this rare. The termination is recorded in the status field; the registry record itself describes only the intended comparison.
Target Phenotypes: Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT02110069 SUPPORT Human Clinical
"In this research study, the study doctor will compare two different drugs to see which one will work better to help shrink your vascular tumor."
Establishes that the head-to-head vincristine-versus-sirolimus comparison was actually attempted, which is what makes its terminated status informative about the evidence base rather than merely absent.
NCT04775173 PHASE_II COMPLETED
High- against low-dose sirolimus, 79 participants. A dosing question, not an efficacy question: sirolimus is assumed to work and the trial asks how much is needed.
Target Phenotypes: Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT04775173 SUPPORT Human Clinical
"The purpose of this study is to compare the efficacy and safety of different concentration gradients of sirolimus in the treatment of Kaposiform hemangioendothelioma."
States the trial as a comparison between sirolimus concentrations, which is what places it as a dose-finding rather than efficacy study.
NCT04077515 PHASE_IV COMPLETED
Low-dose sirolimus in Chinese children, 92 participants, randomised and open-label.
Target Phenotypes: Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT04077515 SUPPORT Human Clinical
"to evaluate the safety and efficacy of Low-dose sirolimus in Kaposiform Hemangioendothelioma in Chinese children by a prospective, randomized open trial."
States the population and design.
NCT04448873 PHASE_IV COMPLETED
Guided discontinuation against maintenance sirolimus, 30 participants. The only registered trial addressing when treatment can stop.
Target Phenotypes: Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT04448873 SUPPORT Human Clinical
"This randomized controlled trial aims to compare guided discontinuation with maintenance treatment of sirolimus in pediatric patients with KHE."
States the discontinuation-versus-maintenance question, which is the stopping decision no other trial here covers.
{ }

Source YAML

click to show 
name: Kasabach-Merritt Syndrome
creation_date: '2026-09-05T17:15:00Z'
description: >-
  A life-threatening consumptive coagulopathy that arises inside a vascular
  tumour and nowhere else. Profound thrombocytopenia, hypofibrinogenemia and a
  rising D-dimer appear in an infant with an enlarging purpuric mass, and the
  platelets are not being destroyed in the circulation but trapped and consumed
  within the lesion itself. The tumour is kaposiform hemangioendothelioma, or
  less often tufted angioma, and the two are regarded as one neoplastic
  spectrum. Ordinary infantile hemangioma does not do this. The modern
  literature prefers "Kasabach-Merritt phenomenon" precisely because the entity
  is a complication of a specific tumour rather than an independent inherited
  syndrome; the name kept here is the MONDO label. The initiating lesion of the
  tumour is unknown in most cases, so this pathograph begins at the abnormal
  vascular bed and follows the platelet.
categories:
- Vascular Tumour Complication
- Consumptive Coagulopathy
- Paediatric Vascular Anomaly
parents:
- blood coagulation disease
- vascular neoplasm
synonyms:
- Kasabach-Merritt phenomenon
- KMP
- Kasabach-Merritt coagulopathy
- thrombocytopenic coagulopathy of kaposiform hemangioendothelioma
prevalence:
- population: Children, Massachusetts
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.071
  notes: >-
    Incidence of the underlying tumour, kaposiform hemangioendothelioma, not of
    the coagulopathy. The source states that the true figure is probably higher
    because small asymptomatic lesions go unreported.
  evidence:
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In Massachusetts, the annual prevalence and incidence have been estimated at
      0.91 and 0.071 per 100,000 children, respectively'
    explanation: Gives the incidence figure and the population it was measured in.
- population: Children with kaposiform hemangioendothelioma, single Chinese centre, 2017-2022
  measure_type: PERIOD_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  notes: >-
    The fraction of the underlying tumour that goes on to the coagulopathy. This
    is a surgical referral cohort of 70 patients, so it sits at the high end;
    reviews give a wider range across series.
  evidence:
  - reference: PMID:38903724
    reference_title: Treatment experience for different risk groups of Kaposiform hemangioendothelioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Of the total cohort, 78% developed KMP; the median age at which thrombocytopenia
      occurred was 27.8 days.'
    explanation: Gives the proportion of the tumour cohort developing the coagulopathy and the
      age at which it declares itself.
pathophysiology:
- name: Abnormal Angiogenic and Lymphangiogenic Tumour Vasculature
  biological_scale: TISSUE
  description: >-
    The lesion is built of infiltrating nodules of spindled endothelial cells
    forming slit-like blood channels and malformed lymphatic channels. Abnormal
    angiogenesis and lymphangiogenesis are its defining pathological features.
    What starts the process is not known, and the review that is the main source
    for this entry says so plainly. A somatic activating GNA14 variant is found
    in a minority of specimens and is not required.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  - preferred_term: lymphatic endothelial cell
    term:
      id: CL:0002138
      label: endothelial cell of lymphatic vessel
  biological_processes:
  - preferred_term: angiogenesis
    modifier: INCREASED
    term:
      id: GO:0001525
      label: angiogenesis
  - preferred_term: lymphangiogenesis
    modifier: INCREASED
    term:
      id: GO:0001946
      label: lymphangiogenesis
  evidence:
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The main pathological features of KHE are abnormal angiogenesis and lymphangiogenesis.
    explanation: States the two processes that define the lesion this node describes.
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The initiating mechanism during the pathogenesis of KHE has yet to be discovered.
    explanation: Records the honest state of knowledge upstream of this node, which is why the
      pathograph starts here rather than at a genetic lesion.
  downstream:
  - target: Intralesional Platelet Trapping and Activation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The abnormal channels trap platelets. Podoplanin on the lesional
      endothelium and CLEC-2 on the platelet are the best characterised route,
      with exposed matrix a second proposed one.
    evidence:
    - reference: PMID:32014025
      reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The C-type lectin-like receptor-2 (CLEC-2) expressed on platelets is an endogenous
        receptor of podoplanin, which in turn is widely expressed in ECs within the KHE lesions
      explanation: Names the receptor-ligand pair that connects the abnormal endothelium of the
        upstream node to the platelet trapping of the downstream one.
- name: Podoplanin-CLEC-2 Platelet Adhesion Signalling
  biological_scale: MOLECULAR
  description: >-
    Podoplanin is widely expressed on the endothelium inside the lesion. It
    binds platelet CLEC-2, and the signal runs through Src family kinases to
    activate the platelet. The pathway is credible and incomplete: podoplanin is
    also highly expressed in lymphatic malformations, and those lesions do not
    aggregate platelets. Something further about the architecture or the flow is
    required.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: platelet activation
    modifier: INCREASED
    term:
      id: GO:0030168
      label: platelet activation
  evidence:
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Binding of podoplanin to CLEC-2 can transmit platelet activation signals via Src
      family kinases, which may account for platelet aggregation in KHE
    explanation: States the signalling route this node asserts, and its own hedge.
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Podoplanin is highly expressed in dysmorphic vessels within the lymphatic malformations,
      but no obvious platelet aggregation occurs in these lesions
    explanation: The negative comparison that keeps this node from being written as sufficient.
      Podoplanin expression alone does not produce the phenomenon.
  - reference: PMID:37307200
    reference_title: Platelet functional abnormalities in pediatric patients with kaposiform
      hemangioendothelioma/Kasabach-Merritt phenomenon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In KHE/KMP, platelet responses induced by CLEC-2 or GPVI activation are impaired
      because of the diminished number of receptors on the platelet surface. This impairment
      correlates with the severity of the disease and resolves as the patient recovers.'
    explanation: Measures the receptor on circulating platelets in patients and finds it depleted
      in proportion to disease severity, recovering with treatment. That is what chronic
      engagement of CLEC-2 inside the lesion would be expected to do, and it ties this node to
      the clinical course.
  downstream:
  - target: Intralesional Platelet Trapping and Activation
    causal_link_type: DIRECT
    description: Receptor engagement is the proximal activating signal for the trapped platelet.
    evidence:
    - reference: PMID:32014025
      reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Binding of podoplanin to CLEC-2 can transmit platelet activation signals via Src
        family kinases, which may account for platelet aggregation in KHE
      explanation: Connects the receptor pair directly to platelet aggregation within the lesion.
- name: Intralesional Platelet Trapping and Activation
  biological_scale: CELLULAR
  description: >-
    Platelets are held inside the tumour vasculature, activated, and aggregated.
    This is the pivot of the whole disease. Trapping alone is not the disease:
    it is seen histologically in lesions that never develop the coagulopathy, so
    it is necessary and not sufficient.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: platelet aggregation
    modifier: INCREASED
    term:
      id: GO:0070527
      label: platelet aggregation
  evidence:
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Intralesional platelet trapping is followed by the activation and aggregation of
      platelets, which then results in activation of the coagulation cascade with subsequent
      consumption of clotting factors.'
    explanation: States the node and the step that follows it.
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Platelet trapping has been revealed histologically in KHE with or without KMP
    explanation: Establishes that trapping occurs in tumours that never produce the coagulopathy,
      which is why this node is described as necessary rather than sufficient.
  downstream:
  - target: Shear-Driven Amplification Loop
    causal_link_type: DIRECT
    description: Microvascular thrombi obstruct flow, and the disturbed flow activates more platelets.
    evidence:
    - reference: PMID:32014025
      reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'In KHE, the thrombi in the microvasculature cause vessel occlusion and prevent
        normal blood flow, all of which can lead to elevated shear stress.'
      explanation: States the step from thrombus to elevated shear that this edge asserts.
  - target: Consumptive Coagulopathy
    causal_link_type: DIRECT
    description: Aggregation activates the coagulation cascade and consumes clotting factors.
    evidence:
    - reference: PMID:32014025
      reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Intralesional platelet trapping is followed by the activation and aggregation of
        platelets, which then results in activation of the coagulation cascade with subsequent
        consumption of clotting factors.'
      explanation: The sentence states this exact causal step.
- name: Shear-Driven Amplification Loop
  biological_scale: TISSUE
  description: >-
    Thrombi obstruct the small convoluted vessels of the lesion, flow becomes
    turbulent, shear rises, and high shear activates further platelets through
    von Willebrand factor and its platelet binding sites. The disease feeds
    itself, and this is why the active phase escalates over days.
  biological_processes:
  - preferred_term: platelet activation
    modifier: INCREASED
    term:
      id: GO:0030168
      label: platelet activation
  evidence:
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'With regard to KHE, platelets in circulating blood may become exposed to turbulent
      blood flow and high shear stress that results from the architecture of the small, convoluted
      and thrombus-obstructed vessels within the KHE lesions. This process in turn causes further
      platelet trapping and activation during the active phase of KHE.'
    explanation: States the loop, including that it drives further trapping, which is the claim
      of this node.
  downstream:
  - target: Intralesional Platelet Trapping and Activation
    causal_link_type: DIRECT
    description: >-
      The returning arm of the loop. High shear drives further trapping and
      activation, which is what makes the active phase self-amplifying.
    evidence:
    - reference: PMID:32014025
      reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: This process in turn causes further platelet trapping and activation during the
        active phase of KHE.
      explanation: The source states the feedback direction explicitly.
- name: Consumptive Coagulopathy
  biological_scale: ORGANISM
  description: >-
    Profound thrombocytopenia, falling fibrinogen and a rising D-dimer, produced
    by consumption rather than by marrow failure or immune destruction. Unlike
    disseminated intravascular coagulation, the driving consumption is localised
    to the tumour.
  biological_processes:
  - preferred_term: blood coagulation
    modifier: INCREASED
    term:
      id: GO:0007596
      label: blood coagulation
  evidence:
  - reference: PMID:38903724
    reference_title: Treatment experience for different risk groups of Kaposiform hemangioendothelioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'KHE may develop into the Kasabach-Merritt phenomenon (KMP), which is characterized
      by thrombocytopenia and consumptive coagulopathy.'
    explanation: Defines the node in the terms used here.
  downstream:
  - target: Intralesional Haemorrhage and Tumour Engorgement
    causal_link_type: DIRECT
    description: >-
      Continued aggregation with hypofibrinogenemia and raised D-dimer ends in
      bleeding into the lesion, which is what makes the mass purpuric, warm,
      painful and rapidly larger.
    evidence:
    - reference: PMID:32014025
      reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Continued platelet aggregation, together with coagulopathy and hypofibrinogenemia
        with elevated D-dimer (coagulation markers), eventually result in intralesional hemorrhage,
        which clinically manifests as very purpuric, warm, painful, and rapidly enlarged tumor
        lesion'
      explanation: States the step from coagulopathy to intralesional haemorrhage and names the
        clinical result.
- name: Intralesional Haemorrhage and Tumour Engorgement
  biological_scale: TISSUE
  description: >-
    Bleeding into the tumour. The mass turns deep purple, becomes hot and
    tender, and enlarges over days. Anaemia follows from sequestration, from
    bleeding and from microangiopathic destruction of red cells in the abnormal
    vessels.
  evidence:
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Continued platelet aggregation, together with coagulopathy and hypofibrinogenemia
      with elevated D-dimer (coagulation markers), eventually result in intralesional hemorrhage,
      which clinically manifests as very purpuric, warm, painful, and rapidly enlarged tumor
      lesion'
    explanation: Describes this node and its clinical appearance.
  downstream:
  - target: Local Infiltrative Tissue Destruction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Expansion during the active phase adds to the infiltrative damage the
      tumour is already doing to muscle, joint and bone.
    evidence:
    - reference: PMID:32014025
      reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The progressive expansion of the mass during the active phase of KMP can further
        compromise the vital structures.
      explanation: States that active-phase expansion worsens damage to surrounding structures.
- name: Local Infiltrative Tissue Destruction
  biological_scale: TISSUE
  description: >-
    The tumour infiltrates rather than displaces. Muscle and connective tissue
    are remodelled, joints are eroded, bone is destroyed, and the survivors of
    the acute coagulopathy are left with contracture, scoliosis, chronic pain
    and lymphedema. This arm runs in tumours that never develop the
    coagulopathy at all.
  evidence:
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In some cases, residual KHEs will continue to infiltrate surrounding tissues, erode
      bone and destroy joints.'
    explanation: States the tissue destruction this node describes.
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Even in patients without KMP, musculoskeletal disorders are frequently seen in cases
      involving the extremities, with a majority of these lesions located on or adjacent to joints'
    explanation: Establishes that this arm is not downstream of the coagulopathy alone, which is
      why it is drawn as a separate consequence of the lesion.
phenotypes:
- category: Hematologic
  name: Profound Thrombocytopenia
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    The defining laboratory finding. Median platelet count 24,000 per microlitre
    in a 70-patient cohort, with severe disease usually taken as below 30 x 10^9
    per litre. It begins in the neonatal period, at a median of 27.8 days in
    that series.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:38903724
    reference_title: Treatment experience for different risk groups of Kaposiform hemangioendothelioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The median platelet count of patients who were associated with KMP was 24,000/µL in
      our cohort.
    explanation: Gives the platelet count in the cohort, supporting both the phenotype and its
      severity.
  - reference: PMID:38903724
    reference_title: Treatment experience for different risk groups of Kaposiform hemangioendothelioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Common clinical characteristics included associated coagulation disorder (100%),
      locally aggressive cutaneous blue-purple mass (89%), thrombocytopenia (78%), and local pain
      or joint dysfunction (20%).'
    explanation: Gives the 78% figure in the cohort, which is the basis for the VERY_FREQUENT band
      as applied to the tumour population this entry describes.
- category: Hematologic
  name: Hypofibrinogenemia
  description: >-
    Fibrinogen falls as it is consumed in the lesion. With the platelet count
    and the D-dimer it forms the laboratory triad used to call the phenomenon.
  phenotype_term:
    preferred_term: Hypofibrinogenemia
    term:
      id: HP:0011900
      label: Hypofibrinogenemia
  evidence:
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Currently, KMP is defined as profound thrombocytopenia, together with consumptive
      coagulopathy and hypofibrinogenemia associated only with the vascular tumors, KHE and tufted
      angioma'
    explanation: Places hypofibrinogenemia in the definition of the entity.
- category: Hematologic
  name: Microangiopathic Hemolytic Anemia
  description: >-
    Red cells are destroyed passing through the abnormal, thrombus-obstructed
    vessels of the lesion, adding to the anaemia produced by sequestration and
    intralesional bleeding.
  phenotype_term:
    preferred_term: Microangiopathic hemolytic anemia
    term:
      id: HP:0001937
      label: Microangiopathic hemolytic anemia
  evidence:
  - reference: PMID:34106442
    reference_title: Kaposiform Hemangioendothelioma with Kasabach-Merritt Phenomenon.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The child was moribund with microangiopathic hemolytic anemia, thrombocytopenia,
      and consumptive coagulopathy without sepsis.'
    explanation: Documents the finding alongside the thrombocytopenia and coagulopathy in a case
      of this disease.
- category: Cutaneous
  name: Locally Aggressive Blue-Purple Cutaneous Mass
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    An enlarging, indurated, blue-purple or purpuric mass, most often on a limb
    or the trunk. It becomes warm, swollen and painful as the coagulopathy
    declares itself. Around one lesion in eight has no cutaneous component at
    all, which is why unexplained neonatal thrombocytopenia warrants imaging of
    the chest and abdomen.
  phenotype_term:
    preferred_term: Vascular neoplasm
    term:
      id: HP:0100742
      label: Vascular neoplasm
  evidence:
  - reference: PMID:38903724
    reference_title: Treatment experience for different risk groups of Kaposiform hemangioendothelioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Common clinical characteristics included associated coagulation disorder (100%),
      locally aggressive cutaneous blue-purple mass (89%), thrombocytopenia (78%), and local pain
      or joint dysfunction (20%).'
    explanation: Gives the lesion description and its 89% frequency in the cohort, which supports
      the VERY_FREQUENT band.
- category: Hematologic
  name: Bruising and Bleeding
  description: >-
    Purpura, ecchymoses and, in severe disease, clinically important
    haemorrhage. Bleeding is the usual mode of acute death.
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'KHE lesions with KMP have progressive engorgement and purpura. KMP can lead to
      significant pain and secondary bleeding.'
    explanation: Names purpura and secondary bleeding as features of the phenomenon, which is
      what this phenotype records.
- category: Musculoskeletal
  name: Pain and Joint Dysfunction
  frequency: OCCASIONAL
  description: >-
    Pain at the tumour site during the active phase, and restricted joint
    movement where the lesion sits on or beside a joint. Reported in 20% of a
    70-patient cohort.
  phenotype_term:
    preferred_term: Limitation of joint mobility
    term:
      id: HP:0001376
      label: Limitation of joint mobility
  evidence:
  - reference: PMID:38903724
    reference_title: Treatment experience for different risk groups of Kaposiform hemangioendothelioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Common clinical characteristics included associated coagulation disorder (100%),
      locally aggressive cutaneous blue-purple mass (89%), thrombocytopenia (78%), and local pain
      or joint dysfunction (20%).'
    explanation: Gives the 20% figure that supports both the phenotype and the OCCASIONAL band.
- category: Lymphatic
  name: Lymphedema
  description: >-
    A late consequence, mostly of lesions on the proximal limb near the inguinal
    or axillary nodes. Mechanical obstruction of lymphatic flow during the acute
    phase is the proposed route.
  phenotype_term:
    preferred_term: Lymphedema
    term:
      id: HP:0001004
      label: Lymphedema
  evidence:
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In this scenario, it is hypothesized that the mechanical obstruction of the lymphatic
      flow during the acute phase of KMP may eventually lead to lymphedema'
    explanation: States the phenotype and, as a hypothesis, its proposed mechanism. The hedge is
      the source's own.
- category: Hematologic
  name: Anemia
  frequency: VERY_FREQUENT
  description: >-
    Anemia accompanies the falling platelet count in almost all patients. It
    is separate from the microangiopathic haemolysis already curated: blood is
    also sequestered in, and lost from, the lesion itself.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:38903724
    reference_title: "Treatment experience for different risk groups of Kaposiform hemangioendothelioma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Almost all patients with KHE have different degrees of anemia at the time platelet level was dropping"
    explanation: "Ties anemia to the period of platelet decline and puts its frequency at almost all patients."
genetic:
- name: GNA14
  gene_term:
    preferred_term: GNA14
    term:
      id: hgnc:4382
      label: GNA14
  relationship_type: SOMATIC_DRIVER
  notes: >-
    A somatic activating c.614A>T (p.Gln205Leu) variant reported in about a
    third of tumour specimens. It is a tumour-level mosaic change, not a
    germline disease allele, and it is neither necessary nor sufficient: a later
    series of seven tumours found none. Nothing about it predicts the
    coagulopathy.
  evidence:
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: mutation was found in 1/3 of KHE specimens and in 1/4 of TA specimens, although these
      studies were weakened by small sample size
    explanation: Gives the frequency of the variant and the source's own caveat about sample size.
  - reference: PMID:31887709
    reference_title: Kaposiform hemangioendothelioma and tufted angioma - (epi)genetic analysis including
      genome-wide methylation profiling.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: 'Using next generation sequencing, heterogeneous mutations were found in a subset of
      cases (2/7) without the presence of GNA14 mutations, previously reported in KHE and TA.'
    explanation: A negative series. Tagged REFUTE against any reading of the variant as a constant
      feature of the tumour, which is why the notes above call it neither necessary nor sufficient.
diagnosis:
- name: Platelet count, fibrinogen and D-dimer
  description: >-
    The laboratory triad. Serial measurement is how the active phase is followed
    and how response to treatment is judged.
  evidence:
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Currently, KMP is defined as profound thrombocytopenia, together with consumptive
      coagulopathy and hypofibrinogenemia associated only with the vascular tumors, KHE and tufted
      angioma'
    explanation: Gives the platelet count and fibrinogen limbs of this assessment as the defining
      laboratory findings.
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Continued platelet aggregation, together with coagulopathy and hypofibrinogenemia
      with elevated D-dimer (coagulation markers), eventually result in intralesional hemorrhage,
      which clinically manifests as very purpuric, warm, painful, and rapidly enlarged tumor
      lesion'
    explanation: Names the D-dimer limb and calls these coagulation markers, which is the third
      measurement in this assessment.
- name: Doppler ultrasound and contrast-enhanced MRI
  description: >-
    Imaging establishes the extent of the lesion, which physical examination
    understates because the tumour infiltrates. Ultrasound serves superficial
    lesions; contrast MRI is the modality that maps deep involvement and is
    what makes a lesion visible when there is no cutaneous component to see.
    This is the assessment the cutaneous-mass phenotype refers to when it says
    unexplained neonatal thrombocytopenia warrants imaging of the chest and
    abdomen.
  evidence:
  - reference: PMID:32014025
    reference_title: "Kaposiform hemangioendothelioma: current knowledge and future perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ultrasound is the modality of choice for small and superficial lesions"
    explanation: "Gives ultrasound its scope: the superficial lesion, not the deep one."
  - reference: PMID:32014025
    reference_title: "Kaposiform hemangioendothelioma: current knowledge and future perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI with and without gadolinium has the most value in the diagnosis of KHE as well as for clearly determining the extent of involvement and response to treatment"
    explanation: "States why MRI carries the diagnostic weight here, and that it is also what tracks treatment response."
  - reference: PMID:32014025
    reference_title: "Kaposiform hemangioendothelioma: current knowledge and future perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI scan of the abdomen and chest should be recommended for such patients"
    explanation: "The source recommendation behind the chest and abdominal imaging that this entry asserts in the cutaneous-mass phenotype description."
- name: Lesional biopsy with immunohistochemistry
  description: >-
    The reference standard, and the assessment that settles the differential
    against infantile hemangioma by GLUT1 staining. It is qualified rather
    than recommended outright: biopsy can worsen a severe coagulopathy, which
    is why the diagnosis is often made on clinical and imaging grounds
    instead.
  evidence:
  - reference: PMID:32014025
    reference_title: "Kaposiform hemangioendothelioma: current knowledge and future perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biopsy is gold standard for diagnosis and should be performed if possible and safe."
    explanation: "Establishes biopsy as the reference standard, with the safety condition attached in the same sentence."
  - reference: PMID:32014025
    reference_title: "Kaposiform hemangioendothelioma: current knowledge and future perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biopsy is frequently not possible or recommended in KHE with severe KMP, and can potentially worsen the coagulopathy."
    explanation: "The reason this assessment is often deferred. Recorded so the entry does not present biopsy as routinely available in severe disease."
  - reference: PMID:32014025
    reference_title: "Kaposiform hemangioendothelioma: current knowledge and future perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunohistochemical staining shows that endothelial cells in KHE lesions are positive both for vascular endothelial markers CD31 and CD34, lymphatic endothelial marker VEGFR-3, D2–40, lymphatic endothelial hyaluronan receptor-1 and Prox-1, but negative for glucose transporter-1(Glut-1) and human herpes virus-8 staining"
    explanation: "The immunophenotype. The GLUT1-negative limb is the discriminator that differential_diagnoses already uses against infantile hemangioma."
differential_diagnoses:
- name: Infantile hemangioma
  description: >-
    The commonest misdiagnosis and the most consequential. Infantile hemangioma
    is GLUT1-positive and does not produce the coagulopathy. Historic reports
    attributing Kasabach-Merritt to it were wrong.
  distinguishing_features:
  - GLUT1 positive on immunohistochemistry
  - Does not cause consumptive coagulopathy
  evidence:
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Currently, KMP is defined as profound thrombocytopenia, together with consumptive
      coagulopathy and hypofibrinogenemia associated only with the vascular tumors, KHE and tufted
      angioma'
    explanation: The word "only" is the discriminating claim. The phenomenon belongs to these two
      tumours and not to infantile hemangioma.
- name: Kaposiform lymphangiomatosis
  description: >-
    Multifocal thoracic and osseous lymphatic disease. It carries a somatic NRAS
    p.Q61R variant that is absent from kaposiform hemangioendothelioma, which
    gives a molecular means of separating them, and it does worse.
  distinguishing_features:
  - Somatic NRAS p.Q61R present
  - Multifocal thoracic and osseous involvement
  evidence:
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: variant (c.182 A > G, p. Q61R) was recently identified in patients with KLA but was
      absent in KHE samples, thus providing a molecular means to further differentiate these two
      entities
    explanation: States the molecular discriminator between the two entities.
treatments:
- name: Sirolimus
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    An mTOR inhibitor, and the drug that changed the outlook for this disease.
    It acts on the tumour rather than on the platelet, which is the right place:
    the coagulopathy stops when the lesion stops. A prospective multicentre
    phase II trial in 126 children with complicated vascular anomalies found
    77.8% objective response, with rates above 80% in the kaposiform
    hemangioendothelioma subgroup. Serious adverse events occurred, including
    grade 4 pneumonitis, and two patients in a separate surgical cohort stopped
    the drug for severe pneumonia.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
  target_mechanisms:
  - target: Abnormal Angiogenic and Lymphangiogenic Tumour Vasculature
    treatment_effect: INHIBITS
    description: >-
      mTOR sits downstream of the VEGF-C/VEGFR-3 and Ang-2/Tie-2 signalling that
      drives the lesion's lymphangiogenesis, so inhibiting it acts on the
      abnormal vascular bed itself.
    evidence:
    - reference: PMID:32014025
      reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'The binding of VEGF-C can stimulate the activation of VEGFR-3 and induce downstream
        PI3K/Akt/mTOR signaling, which mediates lymphangiogenesis.'
      explanation: Places mTOR in the pathway that produces the abnormal vasculature, which is why
        the drug is drawn as inhibiting this node.
  evidence:
  - reference: PMID:34082006
    reference_title: A prospective multicenter study of sirolimus for complicated vascular anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Of 126 patients enrolled on an intention-to-treat basis, 98 (77.8%) had had an
      objective response to sirolimus, with a ≥20% decrease in lesion volume.'
    explanation: The prospective trial result behind this treatment.
  - reference: PMID:34082006
    reference_title: A prospective multicenter study of sirolimus for complicated vascular anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'More serious adverse events included reversible grade 4 pneumonitis in 3 patients
      and grade 4 upper respiratory infection in 1 patient.'
    explanation: Records the toxicity of the drug from the same trial, which is what makes the
      pneumonia deaths reported elsewhere credible rather than incidental.
- name: Corticosteroid Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    High-dose corticosteroid, commonly methylprednisolone 5 to 6 mg/kg daily,
    used first or alongside sirolimus. Response is partial and unreliable: 36%
    of 55 patients with the coagulopathy in one cohort were steroid-sensitive.
    That is why it is not used alone in severe disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisolone
      term:
        id: CHEBI:8378
        label: prednisolone
  target_mechanisms:
  - target: Consumptive Coagulopathy
    treatment_effect: MODULATES
    description: >-
      Steroid is given to bring the platelet count up in the acute phase. The
      mechanism by which it does so in this disease is not established, and the
      response rate is low, so the edge is graded as modulating rather than
      inhibiting.
    evidence:
    - reference: PMID:38903724
      reference_title: Treatment experience for different risk groups of Kaposiform hemangioendothelioma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'In 55 patients with KMP, 36% were sensitive to high-dose corticosteroid therapy.'
      explanation: Gives the response rate in patients with the coagulopathy, which is the claim
        this edge makes and the reason it is not graded as inhibition.
  evidence:
  - reference: PMID:38903724
    reference_title: Treatment experience for different risk groups of Kaposiform hemangioendothelioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Ninety-two percent of patients were given surgery treatment and 89% of these patients
      were given high-dose methylprednisolone (5-6 mg/kg daily) before surgery.'
    explanation: Documents the agent, the dose and its use before surgery in this cohort.
- name: Vincristine
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    A vinca alkaloid, long recommended with corticosteroid by the 2013 consensus
    statement and still used where sirolimus fails or is not tolerated. The
    recommendation rests on expert opinion, not on trials, and the review that
    reports it says so. That gap is not for want of trying: NCT02110069 was a
    randomised head-to-head comparison of vincristine against sirolimus and
    terminated with four participants enrolled, so the comparison this
    recommendation needs was attempted and could not accrue.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: vincristine
      term:
        id: CHEBI:28445
        label: vincristine
  target_mechanisms:
  - target: Abnormal Angiogenic and Lymphangiogenic Tumour Vasculature
    treatment_effect: INHIBITS
    description: Cytotoxic action against the proliferating tumour.
    evidence:
    - reference: PMID:32014025
      reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Medical treatments with corticosteroids and/or vincristine have been recommended
        for the management of KHE.
      explanation: Establishes the drug's place in management of the tumour, which is the node
        this edge points at.
  evidence:
  - reference: PMID:32014025
    reference_title: 'Kaposiform hemangioendothelioma: current knowledge and future perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'However, these recommendations are based on expert opinion rather than rigorous
      clinical studies.'
    explanation: The source's own grading of the evidence behind the corticosteroid and vincristine
      recommendations. Recorded here so the entry does not overstate them.
- name: Surgical Resection
  therapeutic_modality: SURGERY
  description: >-
    Complete resection can cure a localised lesion. In one cohort all eight
    low-risk patients who were operated on recovered without recurrence over up
    to five years of follow-up. Active severe coagulopathy makes surgery
    hazardous, so it is usually preceded by medical control.
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Abnormal Angiogenic and Lymphangiogenic Tumour Vasculature
    treatment_effect: INHIBITS
    description: Removes the vascular bed in which platelets are trapped.
    evidence:
    - reference: PMID:38903724
      reference_title: Treatment experience for different risk groups of Kaposiform hemangioendothelioma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Patients from the low-risk group (eight cases) underwent operation, all of whom
        recovered without recurrence after a maximum follow-up of 5 years.'
      explanation: Removing the lesion resolved the disease in this group, which is what this edge
        asserts.
  evidence:
  - reference: PMID:38903724
    reference_title: Treatment experience for different risk groups of Kaposiform hemangioendothelioma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Our study describes the largest assessment of high-risk patients with KHE who have
      undergone an operation to date, with 5 years of follow-up to track recovery'
    explanation: Establishes the surgical cohort this treatment entry draws on.
- name: Supportive Transfusion Management
  therapeutic_modality: OTHER
  description: >-
    The management point that follows directly from the trapping node.
    Transfused platelets are consumed by the lesion like endogenous ones, so
    transfusing them does not durably raise the count and is restricted to
    active bleeding or an imminent procedure. Red cells and plasma products
    are the supportive measures that do help, correcting anemia and the
    coagulopathy respectively.
  treatment_term:
    preferred_term: supportive transfusion management
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Consumptive Coagulopathy
    treatment_effect: MODULATES
    description: >-
      Plasma products replace what the lesion consumes. This corrects the
      laboratory abnormality without acting on the tumour that causes it,
      which is why the effect is MODULATES and not INHIBITS.
    evidence:
    - reference: PMID:38903724
      reference_title: "Treatment experience for different risk groups of Kaposiform hemangioendothelioma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "infusion of suspended red blood cells and fresh frozen plasma with cold precipitation to correct anemia and improve coagulation"
      explanation: "Names the blood products used and what each corrects, which is the claim this edge makes."
  evidence:
  - reference: PMID:32014025
    reference_title: "Kaposiform hemangioendothelioma: current knowledge and future perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Platelet transfusion should not be used unless the patient is actively bleeding or in preparation for surgery."
    explanation: "The restriction itself, with the two exceptions that permit platelet transfusion."
  - reference: PMID:38903724
    reference_title: "Treatment experience for different risk groups of Kaposiform hemangioendothelioma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Platelet transfusion alone was not effective for KMP cases as platelet counts dropped rapidly to previous levels within 48 h."
    explanation: "The observation behind the restriction: transfused platelets are consumed within 48 hours, so the transfusion does not hold."
clinical_trials:
- name: NCT03188068
  phase: PHASE_II
  status: COMPLETED
  description: >-
    The only registered trial scoped to the coagulopathy rather than to the
    tumour alone: sirolimus against sirolimus plus prednisolone in kaposiform
    hemangioendothelioma with Kasabach-Merritt phenomenon. Completed with 30
    participants.
  target_phenotypes:
  - preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: clinicaltrials:NCT03188068
    reference_title: "Sirolimus Versus Sirolimus Plus Prednisolone for Kaposiform Hemangioendothelioma With Kasabach-Merritt Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of this study is to compare the efficacy and safety of orally administered sirolimus versus sirolimus plus pednisolone in the treatment of KHE associated with KMP."
    explanation: "States the comparison and, unusually among these trials, scopes it to KHE associated with KMP rather than to the tumour generally."
- name: NCT02110069
  phase: PHASE_II
  status: TERMINATED
  description: >-
    The head-to-head vincristine against sirolimus comparison. It terminated
    with four participants enrolled, which is the concrete reason the
    vincristine recommendation still rests on expert opinion: the trial that
    would have settled it could not accrue in a disease this rare. The
    termination is recorded in the status field; the registry record itself
    describes only the intended comparison.
  target_phenotypes:
  - preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: clinicaltrials:NCT02110069
    reference_title: "A Randomized Phase 2 Study of Vincristine Versus Sirolimus to Treat High Risk Kaposiform Hemangioendothelioma (KHE)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this research study, the study doctor will compare two different drugs to see which one will work better to help shrink your vascular tumor."
    explanation: "Establishes that the head-to-head vincristine-versus-sirolimus comparison was actually attempted, which is what makes its terminated status informative about the evidence base rather than merely absent."
- name: NCT04775173
  phase: PHASE_II
  status: COMPLETED
  description: >-
    High- against low-dose sirolimus, 79 participants. A dosing question,
    not an efficacy question: sirolimus is assumed to work and the trial asks
    how much is needed.
  target_phenotypes:
  - preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: clinicaltrials:NCT04775173
    reference_title: "Efficacy and Safety of High- vs Low-Dose Sirolimus in Patients With Kaposiform Hemangioendothelioma: A Trial Protocol"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of this study is to compare the efficacy and safety of different concentration gradients of sirolimus in the treatment of Kaposiform hemangioendothelioma."
    explanation: "States the trial as a comparison between sirolimus concentrations, which is what places it as a dose-finding rather than efficacy study."
- name: NCT04077515
  phase: PHASE_IV
  status: COMPLETED
  description: >-
    Low-dose sirolimus in Chinese children, 92 participants, randomised and
    open-label.
  target_phenotypes:
  - preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: clinicaltrials:NCT04077515
    reference_title: "Safety and Efficacy of Low-dose Sirolimus to Kaposiform Hemangioendothelioma:A Prospective, Randomized Open Trial"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "to evaluate the safety and efficacy of Low-dose sirolimus in Kaposiform Hemangioendothelioma in Chinese children by a prospective, randomized open trial."
    explanation: "States the population and design."
- name: NCT04448873
  phase: PHASE_IV
  status: COMPLETED
  description: >-
    Guided discontinuation against maintenance sirolimus, 30 participants.
    The only registered trial addressing when treatment can stop.
  target_phenotypes:
  - preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: clinicaltrials:NCT04448873
    reference_title: "Guided Discontinuation Versus Maintenance Treatment of Sirolimus in Pediatric Patients With Kaposiform Hemangioendothelioma: a Randomized Controlled Trial"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This randomized controlled trial aims to compare guided discontinuation with maintenance treatment of sirolimus in pediatric patients with KHE."
    explanation: "States the discontinuation-versus-maintenance question, which is the stopping decision no other trial here covers."
progression:
- phase: Lesion present at or soon after birth
  age_range: Birth to first year
  notes: >-
    The tumour is congenital or near-congenital in most cases. The
    coagulopathy is not present from the outset; it develops within the
    lesion afterwards.
  evidence:
  - reference: PMID:32014025
    reference_title: "Kaposiform hemangioendothelioma: current knowledge and future perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approximately 50% of cutaneous lesions are visible or detectable at birth"
    explanation: "Puts half of cutaneous lesions at birth, establishing this as the starting phase."
  - reference: PMID:32014025
    reference_title: "Kaposiform hemangioendothelioma: current knowledge and future perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The distribution of age at onset has one peak within the first year of life when approximately 90% of KHE are evident."
    explanation: "Bounds the onset window for the tumour as a whole."
- phase: Active Kasabach-Merritt phase
  age_range: First days to months of life
  notes: >-
    The phase the pathograph models. The lesion enlarges and becomes engorged
    and purpuric as platelets are trapped, which is the visible correlate of
    the trapping and haemorrhage nodes rather than growth of tumour bulk.
  evidence:
  - reference: PMID:32014025
    reference_title: "Kaposiform hemangioendothelioma: current knowledge and future perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KHE tumors that develop KMP will appear to ‘grow’ and become engorged and purpuric in the first days/weeks/months of life"
    explanation: "Describes the enlargement and purpuric change as the presentation of the phenomenon, and places it in the first days to months."
- phase: Chronic residual phase
  notes: >-
    Survival of the acute phase does not end the disease. Residual tumour
    continues to infiltrate, and fibrosis is the pathological end state, which
    is what links the infiltrative-destruction arm of the pathograph to the
    lasting musculoskeletal and lymphatic morbidity.
  evidence:
  - reference: PMID:32014025
    reference_title: "Kaposiform hemangioendothelioma: current knowledge and future perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In some cases, residual KHEs will continue to infiltrate surrounding tissues, erode bone and destroy joints."
    explanation: "States that residual lesions keep infiltrating and destroying bone and joint after the acute phase."
  - reference: PMID:32014025
    reference_title: "Kaposiform hemangioendothelioma: current knowledge and future perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathologically, untreated KHE lesions are characterized by progressive fibrosis"
    explanation: "Names fibrosis as the pathological end state of untreated lesions."
  - reference: PMID:32014025
    reference_title: "Kaposiform hemangioendothelioma: current knowledge and future perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lymphedema may be a potential sequela of KHE, particularly tumor involving the legs"
    explanation: "Records lymphedema as a chronic sequela, matching the phenotype already curated."
histopathology:
- name: Infiltrating nodules of spindle endothelial cells
  description: >-
    The architectural hallmark. The nodules are infiltrative rather than
    encapsulated, which is the histological form of the invasive growth the
    first pathophysiology node describes.
  finding_term:
    preferred_term: infiltrating nodules of spindle endothelial cells
  evidence:
  - reference: PMID:32014025
    reference_title: "Kaposiform hemangioendothelioma: current knowledge and future perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The histologic hallmark of KHE is infiltrating, defined, rounded and confluent nodules, which are composed of spindle endothelial cells."
    explanation: "States the hallmark and its cellular composition."
- name: Slit-like channels with platelet thrombi and hemosiderin
  description: >-
    The microscopic counterpart of the trapping node: platelet thrombi are
    visible inside the lesion, and the hemosiderin records bleeding that has
    already occurred there.
  finding_term:
    preferred_term: slit-like vascular lumina with intralesional platelet thrombi
  evidence:
  - reference: PMID:32014025
    reference_title: "Kaposiform hemangioendothelioma: current knowledge and future perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These spindle endothelial cells align to form malformed lymphatic channels and slit-like vascular lumina containing erythrocytes, along with platelet thrombi, eosinophilic hyaline bodies and the extravasation of hemosiderin deposits."
    explanation: "Names the platelet thrombi and hemosiderin within the malformed channels, which is the histological evidence for intralesional trapping and haemorrhage."
references:
- reference: PMID:31887709
  title: "Kaposiform hemangioendothelioma and tufted angioma - (epi)genetic analysis including genome-wide methylation profiling."
- reference: PMID:32014025
  title: "Kaposiform hemangioendothelioma: current knowledge and future perspectives."
- reference: PMID:34082006
  title: "A prospective multicenter study of sirolimus for complicated vascular anomalies."
- reference: PMID:34106442
  title: "Kaposiform Hemangioendothelioma with Kasabach-Merritt Phenomenon."
- reference: PMID:37307200
  title: "Platelet functional abnormalities in pediatric patients with kaposiform hemangioendothelioma/Kasabach-Merritt phenomenon."
- reference: PMID:38903724
  title: "Treatment experience for different risk groups of Kaposiform hemangioendothelioma."
- reference: clinicaltrials:NCT02110069
  title: "A Randomized Phase 2 Study of Vincristine Versus Sirolimus to Treat High Risk Kaposiform Hemangioendothelioma (KHE)."
- reference: clinicaltrials:NCT03188068
  title: "Sirolimus Versus Sirolimus Plus Prednisolone for Kaposiform Hemangioendothelioma With Kasabach-Merritt Syndrome"
- reference: clinicaltrials:NCT04077515
  title: "Safety and Efficacy of Low-dose Sirolimus to Kaposiform Hemangioendothelioma:A Prospective, Randomized Open Trial"
- reference: clinicaltrials:NCT04448873
  title: "Guided Discontinuation Versus Maintenance Treatment of Sirolimus in Pediatric Patients With Kaposiform Hemangioendothelioma: a Randomized Controlled Trial"
- reference: clinicaltrials:NCT04775173
  title: "Efficacy and Safety of High- vs Low-Dose Sirolimus in Patients With Kaposiform Hemangioendothelioma: A Trial Protocol"
disease_term:
  preferred_term: Kasabach-Merritt syndrome
  term:
    id: MONDO:0007708
    label: Kasabach-Merritt syndrome
review_notes: >-
  Dataset discovery was run and returned one candidate, geo:GSE124760, matched
  only through the synonym "hemangioma-thrombocytopenia syndrome". It is a
  four-sample mouse study of endothelial p53 in stress-induced vascular
  malignancy, not a study of this disease, and it was not curated.


  Trials. All five trials the deep research surfaced are curated. Their phase,
  status and enrolment were taken from the ClinicalTrials.gov record rather
  than from the research report, which is why NCT02110069 carries
  status TERMINATED although its registry summary text does not mention the
  termination; the summary is what the evidence snippet quotes, and the
  structured status carries the fact. Enrolment counts are not modelled because
  the schema has no slot for them, so they appear in the descriptions.


  Diagnostics. Imaging and biopsy are now modelled. The immunophenotype is
  curated as one evidence item quoting the full marker panel rather than split
  per marker, because the source states it as a single sentence and splitting
  would quote fragments that assert nothing on their own.


  Histopathology terms are left unbound. NCIT was searched for the two
  findings; it has no term for infiltrating spindle-endothelial nodules or for
  slit-like channels carrying platelet thrombi, and the nearest candidate,
  NCIT:C35990 Hemosiderin Deposition, names one component of a finding that is
  about the channels, the thrombi and the hemosiderin together. Binding it
  would assert something narrower than the finding, so both carry a free-text
  preferred_term only.


  Still not modelled, deliberately. Sequencing has no diagnostic role here and
  the research says so, so no molecular assessment is curated. Response
  thresholds used as trial endpoints (platelets above 100,000 per microlitre,
  or twice baseline with fibrinogen above 150 mg/dL) are trial definitions
  rather than clinical reference intervals, and are not curated as
  reference_ranges.
notes: >-
  Terminology. The current literature calls this the Kasabach-Merritt
  phenomenon and reserves "syndrome" for the historical usage, on the grounds
  that it is a complication of a defined tumour rather than a disease in its own
  right. The entry keeps the MONDO label as its name and records the modern term
  as a synonym.
📚

References & Deep Research

References

11
PMID:31887709
Kaposiform hemangioendothelioma and tufted angioma - (epi)genetic analysis including genome-wide methylation profiling.
No top-level findings curated for this source.
PMID:32014025
Kaposiform hemangioendothelioma: current knowledge and future perspectives.
No top-level findings curated for this source.
PMID:34082006
A prospective multicenter study of sirolimus for complicated vascular anomalies.
No top-level findings curated for this source.
PMID:34106442
Kaposiform Hemangioendothelioma with Kasabach-Merritt Phenomenon.
No top-level findings curated for this source.
PMID:37307200
Platelet functional abnormalities in pediatric patients with kaposiform hemangioendothelioma/Kasabach-Merritt phenomenon.
No top-level findings curated for this source.
PMID:38903724
Treatment experience for different risk groups of Kaposiform hemangioendothelioma.
No top-level findings curated for this source.
clinicaltrials:NCT02110069
A Randomized Phase 2 Study of Vincristine Versus Sirolimus to Treat High Risk Kaposiform Hemangioendothelioma (KHE).
No top-level findings curated for this source.
clinicaltrials:NCT03188068
Sirolimus Versus Sirolimus Plus Prednisolone for Kaposiform Hemangioendothelioma With Kasabach-Merritt Syndrome
No top-level findings curated for this source.
clinicaltrials:NCT04077515
Safety and Efficacy of Low-dose Sirolimus to Kaposiform Hemangioendothelioma:A Prospective, Randomized Open Trial
No top-level findings curated for this source.
clinicaltrials:NCT04448873
Guided Discontinuation Versus Maintenance Treatment of Sirolimus in Pediatric Patients With Kaposiform Hemangioendothelioma: a Randomized Controlled Trial
No top-level findings curated for this source.
clinicaltrials:NCT04775173
Efficacy and Safety of High- vs Low-Dose Sirolimus in Patients With Kaposiform Hemangioendothelioma: A Trial Protocol
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record review notes

Dataset discovery was run and returned one candidate, geo:GSE124760, matched only through the synonym "hemangioma-thrombocytopenia syndrome". It is a four-sample mouse study of endothelial p53 in stress-induced vascular malignancy, not a study of this disease, and it was not curated. Trials. All five trials the deep research surfaced are curated. Their phase, status and enrolment were taken from the ClinicalTrials.gov record rather than from the research report, which is why NCT02110069 carries status TERMINATED although its registry summary text does not mention the termination; the summary is what the evidence snippet quotes, and the structured status carries the fact. Enrolment counts are not modelled because the schema has no slot for them, so they appear in the descriptions. Diagnostics. Imaging and biopsy are now modelled. The immunophenotype is curated as one evidence item quoting the full marker panel rather than split per marker, because the source states it as a single sentence and splitting would quote fragments that assert nothing on their own. Histopathology terms are left unbound. NCIT was searched for the two findings; it has no term for infiltrating spindle-endothelial nodules or for slit-like channels carrying platelet thrombi, and the nearest candidate, NCIT:C35990 Hemosiderin Deposition, names one component of a finding that is about the channels, the thrombi and the hemosiderin together. Binding it would assert something narrower than the finding, so both carry a free-text preferred_term only. Still not modelled, deliberately. Sequencing has no diagnostic role here and the research says so, so no molecular assessment is curated. Response thresholds used as trial endpoints (platelets above 100,000 per microlitre, or twice baseline with fibrinogen above 150 mg/dL) are trial definitions rather than clinical reference intervals, and are not curated as reference_ranges.

Review round: add clinical trials, imaging and biopsy diagnostics, progression, histopathology · 2026-09-06T03:55:47Z · View source

Addressed the CHANGES_REQUESTED review on PR 11187. Both blocking items and all four suggestions taken in one push. IMPORTANT 1: added clinical_trials with all five trials the deep research surfaced (NCT03188068, NCT02110069, NCT04775173, NCT04077515, NCT04448873); phase, status and enrolment were read from the ClinicalTrials.gov API rather than from the research report, so NCT02110069 carries status TERMINATED although its cached registry summary does not state the termination. IMPORTANT 2: expanded diagnosis from the laboratory triad alone to add Doppler ultrasound with contrast MRI, and lesional biopsy with the GLUT1-negative HHV8-negative immunophenotype, both quoted from the already-cached PMID:32014025; this removes the two places where the entry asserted diagnostics in prose without modelling them. Suggestions taken: Supportive Transfusion Management treatment carrying the platelet-transfusion restriction and the 48-hour consumption observation; progression with three phases; histopathology with two findings; Anemia phenotype bound to HP:0001903. Snippets verified 44/44 to 67/67. All offline gates pass, no baseline widened.

Create: Kasabach-Merritt Syndrome · 2026-09-05T21:38:57Z · View source

New entry for Kasabach-Merritt syndrome (MONDO:0007708), curated from an Edison falcon deep-research report (research/Kasabach-Merritt_Syndrome-deep-research-falcon.md) plus primary literature fetched from PubMed. The pathograph is built as a causal chain from the abnormal angiogenic/lymphangiogenic tumour vasculature of kaposiform hemangioendothelioma through podoplanin-CLEC-2 platelet adhesion, intralesional platelet trapping and activation, a shear-driven amplification loop that feeds back onto trapping, consumptive coagulopathy, intralesional haemorrhage, and a separate infiltrative tissue-destruction arm that runs in tumours without the coagulopathy. Seven phenotypes, four treatments (sirolimus, corticosteroid, vincristine, resection), two differential diagnoses, GNA14 recorded as a somatic driver with an explicit negative series (PMID:31887709) tagged REFUTE against reading it as a constant feature. Validated with 'just validate' (schema, terms, references): 43/43 snippets verified against cached references, no term errors. check-entity-refs, check-duplicate-keys and check-title-snippets all pass. Compliance 99.1% global / 100.0% weighted; the only gap is datasets, and the dataset-discovery disposition is recorded in review_notes. Two evidence items initially carried a fabricated title and snippet for PMID:30655857; the reference validator caught both and they were replaced with real quotes from other cached papers.

Falcon ▸
Kasabach–Merritt Syndrome/Phenomenon: Disease Characteristics Report
Edison Scientific Literature 20 citations 2026-09-05T17:23:56.518815

Kasabach–Merritt Syndrome/Phenomenon: Disease Characteristics Report

Scope and terminology. The preferred modern term is Kasabach–Merritt phenomenon (KMP) rather than “Kasabach–Merritt syndrome” (KMS). KMP is not an independent inherited disease: it is a severe platelet-consuming coagulopathy arising almost exclusively in kaposiform hemangioendothelioma (KHE) and, less often, tufted angioma (TA). It should not be attributed to ordinary infantile hemangioma. Evidence below is aggregated disease-level literature and trial data, not individual EHR records, except where explicitly identified as a case or case series. The strongest recent source retrieved was a 70-patient 2024 retrospective cohort; much management evidence nevertheless remains observational or expert consensus because the disorder is exceptionally rare. (li2024treatmentexperiencefor pages 1-2, ji2020kaposiformhemangioendotheliomacurrent pages 1-2)

1. Disease information

KMP comprises profound thrombocytopenia caused by intralesional platelet trapping, with consumptive coagulopathy, hypofibrinogenemia, elevated D-dimer and, frequently, microangiopathic or hemorrhagic anemia. The underlying KHE is a rare, locally aggressive vascular neoplasm with combined blood-vascular and lymphatic endothelial differentiation but no usual distant metastasis. TA and KHE are regarded as a clinicopathologic spectrum, with TA generally more superficial and less aggressive. (gasparella2025thevascernvascadiagnostic pages 2-6, ji2020kaposiformhemangioendotheliomacurrent pages 1-2, NCT03188068 chunk 1)

Identifiers and synonyms

  • MONDO: MONDO:0007708, Kasabach–Merritt syndrome (user-supplied identifier; current clinical terminology favors KMP).
  • MeSH: D059885, Kasabach-Merritt Syndrome, confirmed in ClinicalTrials.gov indexing. (NCT04077515 chunk 1)
  • Synonyms: Kasabach–Merritt phenomenon, Kasabach–Merritt syndrome, KMP, KMS, Kasabach–Merritt coagulopathy, thrombocytopenic coagulopathy associated with KHE/TA.
  • OMIM/Orphanet: no verified syndrome-specific number was established from the retrieved evidence; KMP is better modeled as a complication/phenotype of KHE or TA rather than a Mendelian disease.
  • ICD-10/ICD-11: no uniquely verified KMP code was identified. Coding generally requires the vascular tumor plus thrombocytopenia/coagulopathy codes; local coding authority should be consulted.

The ontology-ready synopsis is:

Domain Core finding Quantitative/current evidence Suggested ontology terms
Definition Kasabach–Merritt phenomenon (KMP; historically “Kasabach–Merritt syndrome”) is a tumor-associated consumptive coagulopathy arising with kaposiform hemangioendothelioma (KHE) or tufted angioma (TA), not infantile or congenital hemangioma. KMP occurs in an estimated 42–71% of KHE; a 2024 KHE cohort found KMP in 55/70 (78%). (ji2020kaposiformhemangioendotheliomacurrent pages 1-2, li2024treatmentexperiencefor pages 1-2, ji2020kaposiformhemangioendotheliomacurrent pages 5-6) MONDO:0007708 Kasabach–Merritt syndrome; MeSH D059885 Kasabach-Merritt Syndrome; candidate: kaposiform hemangioendothelioma; candidate: tufted angioma
Hematologic phenotype Profound thrombocytopenia from intralesional platelet trapping, consumptive coagulopathy, hypofibrinogenemia, elevated D-dimer, and sometimes severe anemia from sequestration or intralesional hemorrhage. Median initial platelet count reported as 21 × 10⁹/L; in the 2024 cohort, median KMP platelet count was 24,000/µL and thrombocytopenia began at median age 27.8 days. Clinically significant severe KMP is generally associated with platelets below 30 × 10⁹/L. (li2024treatmentexperiencefor pages 1-2, ji2020kaposiformhemangioendotheliomacurrent pages 5-6, NCT03188068 chunk 1) HP:0001873 Thrombocytopenia; HP:0011890 Prolonged bleeding time; HP:0001892 Abnormal bleeding; HP:0001903 Anemia; HP:0011900 Hypofibrinogenemia; candidate: elevated D-dimer; candidate: consumptive coagulopathy
Lesion phenotype and anatomy The KHE lesion is typically an enlarging, infiltrative, indurated blue-purple or purpuric mass that becomes warm, swollen, and painful during KMP; deep lesions may lack skin findings. Musculoskeletal infiltration can cause restricted motion, contracture, bone erosion, and chronic pain. In a 2024 cohort, 89% had a locally aggressive blue-purple cutaneous mass and 20% had pain or joint dysfunction; sites were lower extremity 35%, trunk 29%, head/neck 24%, and upper extremity 10%. Approximately 12% may lack cutaneous involvement. (li2024treatmentexperiencefor pages 1-2, ji2020kaposiformhemangioendotheliomacurrent pages 5-6, ji2020kaposiformhemangioendotheliomacurrent pages 6-8) HP:0000969 Edema; HP:0000978 Bruising susceptibility; HP:0002829 Arthralgia; HP:0001376 Limitation of joint mobility; HP:0002653 Bone pain; candidate: painful vascular tumor; UBERON:0002101 limb; UBERON:0002102 forelimb; UBERON:0002103 hindlimb; UBERON:0000479 tissue
Mechanism Dysregulated angiogenesis and lymphangiogenesis form abnormal podoplanin-positive vascular channels. Platelet CLEC-2 engagement by podoplanin and, inferentially, endothelial injury plus high shear/von-Willebrand-factor signaling activate and aggregate platelets. This leads to coagulation-cascade activation, consumption of platelets and clotting factors, intralesional thrombosis/hemorrhage, and clinical KMP. Histologic platelet trapping occurs in KHE with and without KMP. VEGF-C/VEGFR3 and Ang-2/Tie-2 signaling can activate PI3K–AKT–mTOR; elevated Ang-2 falls with sirolimus, but its causal role in KMP remains unproven. (ji2020kaposiformhemangioendotheliomacurrent pages 5-6, ji2020kaposiformhemangioendotheliomacurrent pages 2-5) GO:0001525 angiogenesis; GO:0001946 lymphangiogenesis; GO:0030168 platelet activation; GO:0070527 platelet aggregation; GO:0007596 blood coagulation; GO:0001934 positive regulation of protein phosphorylation; CL:0000115 endothelial cell; CL:0000233 platelet; candidate: lymphatic endothelial cell
Diagnostics Diagnosis integrates lesion behavior, CBC/coagulation studies, Doppler ultrasound, contrast MRI, and—when safe—histopathology. MRI commonly shows an ill-defined, infiltrative, T1-isointense and T2-hyperintense, diffusely enhancing lesion with multiplanar involvement and fat stranding. Biopsy may worsen severe coagulopathy. Initial laboratory evaluation includes platelet count, fibrinogen, and D-dimer. Histology shows infiltrative spindle-endothelial nodules, slit-like channels, platelet thrombi, and hemosiderin; immunophenotype is CD31/CD34/VEGFR3/D2-40/LYVE1/PROX1 positive and GLUT1/HHV8 negative. (gasparella2025thevascernvascadiagnostic pages 2-6, ji2020kaposiformhemangioendotheliomacurrent pages 6-8, ji2020kaposiformhemangioendotheliomacurrent pages 8-10) HP:0001873 Thrombocytopenia; HP:0011900 Hypofibrinogenemia; NCIT candidate: Complete Blood Count; NCIT candidate: Coagulation Study; NCIT candidate: Doppler Ultrasound; NCIT candidate: Magnetic Resonance Imaging; NCIT candidate: Biopsy; CL:0000115 endothelial cell
Treatment Severe KMP generally requires urgent multidisciplinary treatment of the tumor and coagulopathy. Contemporary practice favors systemic sirolimus plus a short corticosteroid course; vincristine is an alternative/add-on for inadequate response or compression. Completely resectable localized disease may be cured surgically, but active extensive KMP makes surgery hazardous. Platelets are reserved for active bleeding or procedures. Common sirolimus initiation is 0.8 mg/m² twice daily with trough 8–15 ng/mL; lower maintenance targets are being studied. Historical response estimates are 94% for sirolimus after prior-treatment failure, 72% for vincristine, and 10–27% for corticosteroid monotherapy. A 2024 surgical cohort reported corticosteroid sensitivity in 36–58%, depending on analysis. (li2024treatmentexperiencefor pages 5-7, NCT03188068 chunk 1, ji2020kaposiformhemangioendotheliomacurrent pages 8-10, ji2020kaposiformhemangioendotheliomacurrent pages 10-12) NCIT:C1212 Sirolimus; NCIT:C769 Prednisolone; NCIT:C933 Vincristine; NCIT candidate: Surgical Resection; NCIT candidate: Embolization; NCIT candidate: Platelet Transfusion; NCIT candidate: Cryoprecipitate Transfusion
Prognosis and evidence gaps Untreated or refractory KMP can cause fatal hemorrhage, hemodynamic instability, vital-structure compression, and organ injury. Survivors may have fibrosis, lymphedema, chronic pain, contractures, impaired mobility, or recurrence. No validated KMP-specific prognostic score, germline inheritance model, preventive intervention, or routine molecular diagnostic test is established. Historical KHE/KMP mortality has been reported as high as 20–30%. In the 2024 cohort, six patients recurred and two died after discharge; two stopped sirolimus because of severe pneumonia. Prospective evidence remains constrained by rarity: a randomized vincristine-versus-sirolimus trial terminated after enrolling only four participants. (li2024treatmentexperiencefor pages 1-2, li2024treatmentexperiencefor pages 5-7, NCT02110069 chunk 1, ji2020kaposiformhemangioendotheliomacurrent pages 6-8) HP:0002721 Immunodeficiency—candidate only for treatment-related susceptibility; HP:0001004 Lymphedema; HP:0001376 Limitation of joint mobility; candidate: chronic pain; candidate: recurrent disease; candidate: treatment-related infection

Table: Compact disease-knowledge-base summary distinguishing KMP from its underlying vascular tumors and mapping established clinical, mechanistic, diagnostic, treatment, and prognostic findings to candidate ontology terms.

2. Etiology, risk and protective factors

Causal factors

The immediate cause is an abnormal KHE/TA vascular bed that traps and activates platelets. The initiating cause of most KHE remains unknown. Almost all cases are sporadic, without a recognized germline, infectious, toxic, dietary or lifestyle cause. Somatic mosaic signaling variants are plausible tumor initiators, but none is necessary or sufficient to diagnose KMP. (ji2020kaposiformhemangioendotheliomacurrent pages 2-5, ji2020kaposiformhemangioendotheliomacurrent pages 1-2)

Risk factors

Established clinical correlates include congenital presentation, young age, large tumor—particularly >8 cm—deep infiltration, and intrathoracic or retroperitoneal location. Tumor size, depth, location and associated hematologic abnormalities also predict complications. Trauma, surgery, infection and post-vaccination inflammation have preceded lesion enlargement or KMP in case reports; these are possible triggers of an existing lesion, not proven primary causes, and routine vaccination itself should not be characterized as causal. Adult KMP is exceptional and has sometimes followed trauma or pregnancy. (ji2020kaposiformhemangioendotheliomacurrent pages 2-5, ji2020kaposiformhemangioendotheliomacurrent pages 5-6)

No reproducible sex, ethnicity, family-history, occupational or lifestyle risk has been established. A 2024 cohort showed only slight male predominance, 38 boys versus 32 girls. (li2024treatmentexperiencefor pages 1-2)

Protective factors and gene–environment interaction

No validated protective allele, diet, lifestyle measure or prophylactic drug is known. The proposed gene–environment model is that a somatic vascular-tumor clone creates susceptibility, while tissue injury or inflammation may increase endothelial activation, blood flow and platelet consumption. This interaction is biologically plausible but has not been demonstrated prospectively. (ji2020kaposiformhemangioendotheliomacurrent pages 2-5)

3. Phenotypes

  • Severe thrombocytopenia: usually neonatal/infantile, acute or rapidly progressive during tumor activation; median initial platelet count reported as 21 ×10⁹/L, and 24 ×10³/µL in the 2024 cohort. Severe KMP is commonly defined by platelets below 30 ×10⁹/L. Suggested HPO: HP:0001873. (li2024treatmentexperiencefor pages 1-2, ji2020kaposiformhemangioendotheliomacurrent pages 5-6, NCT03188068 chunk 1)
  • Consumptive coagulopathy: low fibrinogen, elevated D-dimer/FDP and continued clotting-factor consumption; severe and fluctuating with tumor activity. Suggested HPO: hypofibrinogenemia (HP:0011900), abnormal coagulation profile.
  • Anemia and bleeding: blood sequestration, intralesional hemorrhage and possible microangiopathic hemolysis produce pallor, ecchymoses, petechiae or clinically important bleeding. Suggested HPO: anemia (HP:0001903), abnormal bleeding (HP:0001892), bruising susceptibility (HP:0000978). (li2019localsutureligationassisted pages 1-2, NCT03188068 chunk 1)
  • Tumor findings: an enlarging, indurated blue-purple/purpuric mass that becomes warm, swollen and intensely painful. Deep KHE may have no skin finding—approximately 12% in one synthesis. Suggested HPO: edema (HP:0000969), pain, vascular skin lesion. (ji2020kaposiformhemangioendotheliomacurrent pages 5-6)
  • Functional phenotypes: restricted range of motion, muscular atrophy, fibrosis, flexion contracture, joint subluxation, bone erosion, scoliosis and chronic pain. Suggested HPO: limitation of joint mobility (HP:0001376), scoliosis, bone pain, muscle atrophy. In the 2024 cohort, pain or joint dysfunction occurred in 20%. (li2024treatmentexperiencefor pages 1-2, ji2020kaposiformhemangioendotheliomacurrent pages 6-8)
  • Lymphatic/vital-organ effects: chronic lymphedema, airway compromise, pleural complications or obstructive jaundice depending on site. Suggested HPO: lymphedema (HP:0001004), upper-airway obstruction, jaundice. (ji2020kaposiformhemangioendotheliomacurrent pages 5-6)

Formal per-phenotype prevalence and validated EQ-5D/SF-36 data are unavailable. KHE can substantially impair mobility, routine activities and family functioning; trials have therefore used PedsQL infant/child and Family Impact instruments. (NCT03188068 chunk 1, NCT04775173 chunk 1)

4. Genetic and molecular information

A somatic activating GNA14 c.614A>T (p.Gln205Leu) variant has been reported in approximately one-third of KHE and one-quarter of TA specimens. It can induce growth-factor independence and MAPK/ERK1/2 activation in experimental systems, but sample sizes were small and it has not been shown to directly cause KMP. A 13q14/16p13.3 translocation was reported in 10% of metaphases in a single study. These are tumor-level, presumably mosaic alterations—not germline disease alleles. (ji2020kaposiformhemangioendotheliomacurrent pages 1-2)

No clinically validated ACMG pathogenic germline variant, HGNC-defined causal gene, population allele frequency, carrier frequency, penetrance, modifier gene, founder effect or pharmacogenomic marker exists for KMP. Consequently, ClinVar-style germline classification, inheritance counseling and population carrier screening are not applicable. NRAS p.Gln61Arg, found in kaposiform lymphangiomatosis, was absent from tested KHE and may help distinguish those entities, but is not a KMP marker. (ji2020kaposiformhemangioendotheliomacurrent pages 8-10)

No consistent chromosomal abnormality, DNA-methylation signature, histone modification, repeat expansion or mitochondrial defect has been established. Tumor sequencing remains investigational and may miss low-level mosaicism unless affected tissue is tested.

5. Environmental information

There is no evidence that toxins, radiation, pollution, smoking, alcohol, diet, exercise or occupational exposure initiates KMP. No bacterial, viral, fungal or parasitic agent is causal; KHE is HHV-8-negative. Infection or inflammatory events may exacerbate an existing tumor and coagulopathy. (ji2020kaposiformhemangioendotheliomacurrent pages 6-8)

6. Mechanism and pathophysiology

Ordered causal chain

  1. A sporadic somatic vascular-cell lesion—GNA14 activation in a subset, but unknown in most cases—leads to clonal KHE/TA growth and dysregulated MAPK signaling.
  2. Abnormal endothelial/lymphatic differentiation leads to infiltrative spindle-cell channels expressing CD31/CD34 and lymphatic markers PROX1, podoplanin/D2-40, LYVE1 and VEGFR3.
  3. VEGF-C–VEGFR3 and Ang-2–Tie2 signaling leads to pathological angiogenesis/lymphangiogenesis and PI3K–AKT–mTOR activation; its direct causal role in KMP remains inferred.
  4. Abnormal podoplanin-positive channels lead to platelet adhesion and activation through platelet CLEC-2/Src-family signaling; endothelial injury/exposed matrix provides an additional inferred route.
  5. Platelet-rich microthrombi lead to vessel obstruction, turbulent flow and high shear, which further activate platelets through von Willebrand factor–GPIb-IX/GPIIb-IIIa signaling—an inferred amplification loop.
  6. Persistent platelet aggregation leads to profound thrombocytopenia and coagulation-cascade activation with consumption of fibrinogen and other factors.
  7. Consumptive coagulopathy branches into: (a) intralesional hemorrhage, anemia, purpura, pain and rapid tumor engorgement; and (b) systemic bleeding/hemodynamic instability.
  8. Tumor expansion and chronic platelet/inflammatory signaling lead to compression, ischemic tissue injury, fibrosis, bone/joint destruction, contracture and lymphedema. (ji2020kaposiformhemangioendotheliomacurrent pages 5-6, ji2020kaposiformhemangioendotheliomacurrent pages 2-5, ji2020kaposiformhemangioendotheliomacurrent pages 6-8)

Platelet trapping has been observed histologically in KHE with and without overt KMP, showing that trapping is necessary but not alone sufficient for severe systemic coagulopathy. Podoplanin–CLEC-2 signaling is mechanistically credible, but podoplanin-positive lymphatic malformations do not ordinarily produce the same platelet aggregation, implying additional architecture, flow or endothelial signals. (ji2020kaposiformhemangioendotheliomacurrent pages 5-6)

KHE-derived mesenchymal stromal cells form vascular networks in vitro, express VEGFR3 and produce increased VEGF-C. PROX1 overexpression in mouse hemangioendothelioma cells increases migration, invasiveness, D2-40 and VEGFR3. Serum Ang-2 is elevated in KHE and falls during sirolimus treatment, but this association does not prove Ang-2 causes KMP. (ji2020kaposiformhemangioendotheliomacurrent pages 2-5)

Suggested annotations: GO:0001525 angiogenesis; GO:0001946 lymphangiogenesis; GO:0030168 platelet activation; GO:0070527 platelet aggregation; GO:0007596 blood coagulation; GO terms for MAPK cascade and TOR signaling. Candidate Cell Ontology classes: endothelial cell (CL:0000115), lymphatic endothelial cell, platelet (CL:0000233), mesenchymal stromal cell. Relevant compartments include plasma membrane receptors, cytoplasm and platelet α-granules.

Robust single-cell, spatial-transcriptomic, proteomic, metabolomic, lipidomic or integrated multi-omic KMP signatures were not established in the retrieved evidence. VEGF-A/C/D, IL-6, IL-8 and Ang-1/2 have been prospective exploratory biomarkers, not validated diagnostics. (NCT02110069 chunk 1, NCT03188068 chunk 1)

7. Anatomical structures affected

KHE most often affects skin, subcutaneous connective tissue, fascia and skeletal muscle, with possible periarticular, osseous, retroperitoneal, mediastinal, thoracic or visceral extension. In the 2024 cohort, sites were lower extremity 35%, trunk 29%, head/neck 24%, upper extremity 10%. Approximately 10–12% may lack visible cutaneous disease. (gasparella2025thevascernvascadiagnostic pages 2-6, li2024treatmentexperiencefor pages 1-2, ji2020kaposiformhemangioendotheliomacurrent pages 5-6)

Secondary structures include joints, bone cortex/epiphysis, lymphatic vessels/nodes, airway, pancreas/biliary tract and cardiopulmonary system. Lesions are generally solitary and asymmetric rather than bilaterally distributed. Candidate UBERON annotations should be assigned lesion-by-lesion: skin, subcutaneous tissue, skeletal muscle, limb, thorax, retroperitoneal space, bone and joint. At the subcellular level, no organelle-specific disease defect is established.

8. Temporal development

Approximately 90% of KHE becomes evident in the first year and roughly half of cutaneous lesions are detectable at birth. In the 2024 series, 84% were present at birth, 27% of patients were neonates, and thrombocytopenia began at a median 27.8 days. (li2024treatmentexperiencefor pages 1-2, ji2020kaposiformhemangioendotheliomacurrent pages 2-5)

The active phase may progress over days to weeks with rapid swelling, purpura, pain and falling platelets. Temporary spontaneous softening or platelet recovery can be followed by rebound tumor growth and severe KMP; one documented infant went from 7 to 161 and then 3 ×10⁹/L platelets as the lesion changed. Chronic residual disease may fibrose and continue to cause pain, lymphedema or contracture. (ji2020kaposiformhemangioendotheliomacurrent pages 12-13, ji2020kaposiformhemangioendotheliomacurrent pages 6-8)

The critical intervention window is active KMP, especially platelets <30 ×10⁹/L, falling fibrinogen, bleeding or vital-structure compression. Stable uncomplicated KHE may sometimes be observed, but spontaneous involution is not assumed.

9. Inheritance and population

KMP is sporadic and non-Mendelian. There is no established autosomal dominant/recessive, X-linked or mitochondrial inheritance; penetrance, anticipation, germline mosaicism, consanguinity, founder effects and carrier frequency are therefore not applicable.

Reported KHE prevalence and incidence in Massachusetts were approximately 0.91 per 100,000 and 0.071 per 100,000 children per year, respectively, likely underestimates because small lesions are missed or misclassified. A later expert pathway cited a North American incidence around 0.71 per million; methodological differences and the rarity of disease preclude a precise global estimate. KMP develops in approximately 42–71% of KHE, although the selected 2024 surgical cohort reported 78%. (li2019localsutureligationassisted pages 1-2, ji2020kaposiformhemangioendotheliomacurrent pages 1-2, gasparella2025thevascernvascadiagnostic pages 1-2, ji2020kaposiformhemangioendotheliomacurrent pages 5-6)

Sex distribution is approximately equal with occasional slight male predominance. No reproducible ethnic or geographic enrichment has been shown. Adult disease is very rare.

10. Diagnostics

Clinical and laboratory assessment

Urgently obtain serial CBC/platelets, fibrinogen, D-dimer, PT/aPTT, FDP, hemoglobin, blood film/hemolysis studies, and organ-function tests. A practical KMP diagnosis combines a compatible KHE/TA lesion with marked thrombocytopenia and consumptive coagulopathy. Platelets <30 ×10⁹/L indicate severe disease; one trial defined hematologic response as platelets >100,000/µL or twice baseline plus fibrinogen >150 mg/dL. (NCT02110069 chunk 1, NCT03188068 chunk 1)

Imaging

Doppler ultrasound is useful for superficial lesions and shows an ill-defined hypervascular solid mass. Contrast-enhanced MRI is preferred for mapping deep extent: typical findings are ill-defined margins, multiplanar infiltration, diffuse enhancement, adjacent fat stranding, T1 signal similar to muscle and T2 hyperintensity; dilated fast-flow vessels, edema and adjacent bone/joint injury may occur. Chest/abdominal MRI should be considered in unexplained severe thrombocytopenia when no superficial lesion is evident. (gasparella2025thevascernvascadiagnostic pages 2-6, ji2020kaposiformhemangioendotheliomacurrent pages 6-8)

Biopsy/pathology

Biopsy is the reference standard when safe, but can worsen severe KMP and may be deferred when clinical/imaging findings are characteristic. Histology shows rounded/confluent infiltrative nodules of spindle endothelial cells forming slit-like blood and malformed lymphatic channels, with erythrocytes, platelet thrombi, hyaline bodies, hemosiderin and fibrosis. Typical immunophenotype is CD31+, CD34+, ERG/FLI1+, VEGFR3+, D2-40+, LYVE1+, PROX1+, GLUT1−, HHV8−. (gasparella2025thevascernvascadiagnostic pages 2-6, ji2020kaposiformhemangioendotheliomacurrent pages 6-8, ji2020kaposiformhemangioendotheliomacurrent pages 8-10)

Differential diagnosis

  • Infantile hemangioma: GLUT1-positive and does not cause KMP.
  • Congenital hemangioma: fully formed at birth; RICH involutes, NICH remains stable; any coagulopathy is usually mild and self-limited over 1–2 weeks.
  • Venous malformation: slow-flow channels, localized intravascular coagulopathy but usually less profound thrombocytopenia.
  • Kaposiform lymphangiomatosis: multifocal thoracic/osseous lymphatic disease; may carry NRAS p.Q61R and has poorer reported survival.
  • Sarcoma or metastatic neuroblastoma: must be excluded in atypical deep masses.
  • TA: may be histologically indistinguishable and belongs to the same spectrum, but is usually more superficial/less aggressive. (gasparella2025thevascernvascadiagnostic pages 2-6, ji2020kaposiformhemangioendotheliomacurrent pages 6-8, ji2020kaposiformhemangioendotheliomacurrent pages 8-10)

Routine WES, WGS, germline panels, CMA, karyotyping, FISH, mitochondrial or repeat-expansion testing is not recommended. Targeted sequencing of affected tissue may be research-useful but does not establish or exclude KMP. No population or newborn screening program exists.

11. Outcomes and prognosis

Acute death can result from hemorrhage, rapid tumor expansion, vital-organ compression, tissue destruction or hemodynamic instability. Historical mortality estimates reached 20–30%, although contemporary multidisciplinary care is likely better; the estimate comes from older/selected series, not modern population survival analysis. (NCT02110069 chunk 1)

In the 2024 cohort, six patients recurred and two died at one and three months after discharge. Long-term morbidity includes fibrosis, chronic pain, lymphedema, reduced range of motion, contracture, scoliosis, bone destruction and functional impairment. No reliable 5- or 10-year survival estimate, life-expectancy decrement, validated prognostic score or molecular prognostic biomarker is available. (li2024treatmentexperiencefor pages 5-7, ji2020kaposiformhemangioendotheliomacurrent pages 6-8)

Poor prognostic features include very young age, large/deep tumors, intrathoracic or retroperitoneal disease, platelets <30 ×10⁹/L, severe anemia, low fibrinogen, rapid enlargement and vital-structure involvement. Early hematologic response is favorable, but radiologic involution may require months to years.

12. Treatment

Management belongs in a multidisciplinary vascular-anomalies center. No drug was originally approved specifically for KHE/KMP; systemic uses below are generally off-label. (ji2020kaposiformhemangioendotheliomacurrent pages 1-2, gasparella2025thevascernvascadiagnostic pages 1-2)

Practical strategy

  1. Stabilize: assess bleeding and organ compromise; use packed red cells for symptomatic severe anemia, cryoprecipitate/FFP for active bleeding or marked hypofibrinogenemia.
  2. Avoid routine platelet transfusion: trapped platelets are rapidly consumed; reserve platelets for active bleeding or an imminent procedure, especially when <30 ×10⁹/L. In the 2024 cohort, transfused counts fell again within 48 hours. (li2024treatmentexperiencefor pages 5-7, ji2020kaposiformhemangioendotheliomacurrent pages 8-10)
  3. Treat severe KMP: contemporary expert practice favors sirolimus plus a short course of corticosteroid. A common sirolimus start is 0.8 mg/m² twice daily, adjusted to trough 8–15 ng/mL; prednisolone 2 mg/kg/day can be tapered over 4–6 weeks after stabilization. NCIt candidates: sirolimus, prednisolone, systemic pharmacotherapy. (NCT03188068 chunk 1, ji2020kaposiformhemangioendotheliomacurrent pages 8-10)
  4. Escalate/add vincristine for inadequate response, severe compression or where sirolimus is unsuitable: 0.05 mg/kg weekly in children <10 kg or 1.5 mg/m² in larger patients. NCIt: vincristine. (NCT02110069 chunk 1)
  5. Localized resectable tumor: complete excision can be definitive after correction of coagulopathy. Surgery during uncontrolled extensive KMP is hazardous because of hemorrhage and functional injury. Embolization or sclerotherapy is reserved for selected anatomy and experienced centers. (li2024treatmentexperiencefor pages 9-10, ji2020kaposiformhemangioendotheliomacurrent pages 10-12)

Comparative evidence and outcomes

Historical response estimates were 10–27% for corticosteroid monotherapy, 72% for vincristine, and 94% for sirolimus among patients who had failed or relapsed after previous therapy. These are cross-study observational estimates, not head-to-head modern trials. Steroids can normalize platelets rapidly but sustained response is inconsistent; adverse effects include infection, growth retardation and behavioral change. Vincristine requires intravenous/central access and can cause neurotoxicity. (NCT03188068 chunk 1, ji2020kaposiformhemangioendotheliomacurrent pages 10-12)

The 2024 70-patient cohort used a surgery-heavy strategy: 65/70 underwent surgery, 54 had complete first-operation removal, six recurred and two died. Platelets rose from 38.4×10³/µL at admission to 97.7 after pretreatment, 160.9 one day after surgery and a mean peak of 462.1×10³/µL. Because this was a selected retrospective center cohort, it does not prove surgery is superior to medical therapy. (li2024treatmentexperiencefor pages 5-7)

Sirolimus toxicities include stomatitis/oral mucositis, dyslipidemia, cytopenias, liver-enzyme abnormalities and infection; rare interstitial pneumonitis and Pneumocystis pneumonia may be fatal. Two patients in the 2024 cohort stopped sirolimus because of severe pneumonia. Drug levels, CBC, renal/liver function, lipids, infections and drug interactions require monitoring. (li2024treatmentexperiencefor pages 1-2, ji2020kaposiformhemangioendotheliomacurrent pages 10-12)

Recent trials and implementation

  • NCT03188068, completed phase 2: sirolimus versus sirolimus plus prednisolone; 30 enrolled. It assessed platelets/fibrinogen at two months, MRI volume, symptoms, biomarkers and PedsQL. (NCT03188068 chunk 1)
  • NCT04077515, completed phase 4: 92 children randomized to troughs 7–10 versus >10–15 ng/mL, motivated by possible infection reduction at lower exposure. (NCT04077515 chunk 1)
  • NCT04775173, completed phase 2: 79 patients, trough 5–8 versus 10–15 ng/mL; objective MRI response was ≥20% volume reduction at 12 months. (NCT04775173 chunk 1)
  • NCT04448873, completed phase 4: 30 patients in guided discontinuation versus maintenance after at least two years’ remission; tapering was limited to 10% monthly over at least six months. Results were not available in the retrieved record. (NCT04448873 chunk 1)
  • NCT02110069, randomized sirolimus-versus-vincristine study: terminated after only four participants because KHE/KMP incidence was too rare and sporadic, illustrating why comparative certainty remains low. (NCT02110069 chunk 1)

Topical sirolimus or tacrolimus may help a truly superficial KHE/TA without deep disease, but evidence consists largely of case reports and mostly TA. Gene, cell, RNA and immune therapies have no established role. There is no validated genotype-guided treatment or KMP pharmacogenomic recommendation.

13. Prevention

Primary prevention: none; there is no established modifiable exposure, vaccine, inherited carrier state or prenatal test. Standard immunization should not be withheld solely because post-vaccination exacerbations have appeared in isolated reports.

Secondary prevention: population screening and newborn screening are not justified. For a known KHE/TA, education about rapid enlargement, purpura, pain and bleeding; prompt CBC/fibrinogen/D-dimer testing; baseline MRI; and specialist follow-up can detect KMP early.

Tertiary prevention: avoid nonessential tumor trauma and biopsy during uncontrolled coagulopathy; avoid routine platelet transfusion; promptly treat infection; monitor sirolimus exposure/toxicity; protect joint motion with rehabilitation; and surveil for fibrosis, lymphedema and relapse. Sirolimus tapering should be slow and clinically monitored because optimal duration is unresolved. (ji2020kaposiformhemangioendotheliomacurrent pages 6-8, NCT04448873 chunk 1)

Genetic counseling should explain that current evidence supports a sporadic somatic lesion with negligible known recurrence risk to siblings or offspring, rather than a hereditary syndrome.

14. Other species and natural disease

No well-validated naturally occurring veterinary counterpart of human KHE-associated KMP, breed association, OMIA disorder, zoonotic transmission or cross-species infectious susceptibility was established in the retrieved evidence. Accordingly, NCBI Taxon/VBO breed annotations, veterinary inheritance and transmission fields should be recorded as not established, not negative in principle.

The relevant signaling proteins and platelet pathways are evolutionarily conserved, but conservation alone does not demonstrate a natural animal disease.

15. Models and research gaps

Available models are limited. Mouse hemangioendothelioma cells can form KHE-like intradermal tumors; forced PROX1 increases invasion, migration, podoplanin and VEGFR3. Patient-derived KHE mesenchymal stromal cells support vascular-network formation in vitro and show VEGF-C/VEGFR3 activity. These systems model angiogenic/lymphatic tumor biology but do not fully reproduce infant KMP, systemic platelet consumption, bleeding and chronic musculoskeletal sequelae. (ji2020kaposiformhemangioendotheliomacurrent pages 2-5)

No validated GNA14 knock-in animal that consistently recapitulates KHE plus KMP, patient-derived organoid, humanized platelet model, large CRISPR screen, or mature single-cell/spatial atlas was found. Priorities are: defining the tumor-initiating cell; determining why only some KHEs produce KMP; directly testing podoplanin–CLEC-2 and shear amplification in vivo; identifying predictors of sirolimus resistance/relapse; establishing infant pharmacokinetics and safer troughs; and conducting multicenter natural-history and quality-of-life studies.

Key source notes and exact quotations

  • Ji et al., Orphanet Journal of Rare Diseases, 3 February 2020, PMID 32014025, DOI/URL: https://doi.org/10.1186/s13023-020-1320-1. The abstract states: “The initiating mechanism during the pathogenesis of KHE has yet to be discovered” and identifies abnormal angiogenesis and lymphangiogenesis as its main pathological features. (ji2020kaposiformhemangioendotheliomacurrent pages 1-2)
  • Li et al., Frontiers in Oncology, 5 June 2024, DOI/URL: https://doi.org/10.3389/fonc.2024.1336763. Its abstract reports: “KHE may develop into the Kasabach–Merritt phenomenon (KMP), which is characterized by thrombocytopenia and consumptive coagulopathy.” This is recent primary human cohort evidence, but retrospective and center-specific. (li2024treatmentexperiencefor pages 1-2)
  • Drolet et al., Journal of Pediatrics, July 2013, PMID 23796341, DOI: https://doi.org/10.1016/j.jpeds.2013.03.080, remains a foundational consensus standard, although its recommendations were expert-derived rather than based on large randomized trials. (NCT04077515 chunk 1, ji2020kaposiformhemangioendotheliomacurrent pages 8-10)
  • The newer VASCERN-VASCA pathway, published online 13 December 2025, DOI/URL: https://doi.org/10.1007/s00431-025-06631-6, provides multidisciplinary European expert guidance but is explicitly level-V consensus evidence. (gasparella2025thevascernvascadiagnostic pages 1-2)

Overall conclusion. KMP is best represented in a knowledge base as a life-threatening hematologic complication of KHE/TA, not as a conventional germline syndrome. The most supported mechanism is self-amplifying intratumoral platelet trapping and activation within an abnormal angiogenic/lymphangiogenic vascular bed. Sirolimus plus short-course corticosteroid has become the principal medical strategy for severe disease, but optimal dose, duration and tapering remain unsettled, and much of the quantitative literature is retrospective.

References

  1. (li2024treatmentexperiencefor pages 1-2): Miaomiao Li, Xusheng Wang, Rosalind Kieran, Zheng Wei Sun, Yubin Gong, Hongzhao Lei, Bin Sun, Li Xiao, Yanlin Wang, Song Wang, Zhiyu Li, Luying Wang, Renrong Lv, Feng Xue, Jianfeng Ge, Changxian Dong, and Ran Huo. Treatment experience for different risk groups of kaposiform hemangioendothelioma. Frontiers in Oncology, Jun 2024. URL: https://doi.org/10.3389/fonc.2024.1336763, doi:10.3389/fonc.2024.1336763. This article has 10 citations.

  2. (ji2020kaposiformhemangioendotheliomacurrent pages 1-2): Yi Ji, Siyuan Chen, Kaiying Yang, Chunchao Xia, and Li Li. Kaposiform hemangioendothelioma: current knowledge and future perspectives. Orphanet Journal of Rare Diseases, Feb 2020. URL: https://doi.org/10.1186/s13023-020-1320-1, doi:10.1186/s13023-020-1320-1. This article has 230 citations and is from a peer-reviewed journal.

  3. (gasparella2025thevascernvascadiagnostic pages 2-6): Paolo Gasparella, Emir Q. Haxhija, Rune Andersen, Maria Barea, Eulalia Baselga, Miguel Bejarano Serrano, Sigurd Berger, Annouk Anne Bisdorff, Olivia Boccara, Petra Borgards, Maria Bom-Sucesso, Laurence M. Boon, Anca Maria Cimpean, Andrea Diociaiuti, Veronika Dvorakova, May El Hachem, Sofia Frisk, Nader Ghaffarpour, Annegret Holm, Alan D. Irvine, Mikkel Kaltoft, Friedrich G. Kapp, Olga Koskova, Kristiina Kyrklund, Miguel Madureira, Darius Palionis, Przemysław Przewratil, Bitten Schönewolf-Greulich, Maria-Corina Stanciulescu, Jaroslav Štěrba, Jukka Tolonen, Birute Vaisnyte, Carine van der Vleuten, Dariusz Wyrzykowski, Leo Schultze Kool, and Miikka Vikkula. The vascern-vasca diagnostic and management pathways for kaposiform hemangioendothelioma. European Journal of Pediatrics, Dec 2025. URL: https://doi.org/10.1007/s00431-025-06631-6, doi:10.1007/s00431-025-06631-6. This article has 5 citations and is from a peer-reviewed journal.

  4. (NCT03188068 chunk 1): Yi Ji. Sirolimus Versus Sirolimus Plus Prednisolone for Kaposiform Hemangioendothelioma. West China Hospital. 2017. ClinicalTrials.gov Identifier: NCT03188068

  5. (NCT04077515 chunk 1): Safety and Efficacy of Low-dose Sirolimus to Kaposiform Hemangioendothelioma. Children's Hospital of Fudan University. 2019. ClinicalTrials.gov Identifier: NCT04077515

  6. (ji2020kaposiformhemangioendotheliomacurrent pages 5-6): Yi Ji, Siyuan Chen, Kaiying Yang, Chunchao Xia, and Li Li. Kaposiform hemangioendothelioma: current knowledge and future perspectives. Orphanet Journal of Rare Diseases, Feb 2020. URL: https://doi.org/10.1186/s13023-020-1320-1, doi:10.1186/s13023-020-1320-1. This article has 230 citations and is from a peer-reviewed journal.

  7. (ji2020kaposiformhemangioendotheliomacurrent pages 6-8): Yi Ji, Siyuan Chen, Kaiying Yang, Chunchao Xia, and Li Li. Kaposiform hemangioendothelioma: current knowledge and future perspectives. Orphanet Journal of Rare Diseases, Feb 2020. URL: https://doi.org/10.1186/s13023-020-1320-1, doi:10.1186/s13023-020-1320-1. This article has 230 citations and is from a peer-reviewed journal.

  8. (ji2020kaposiformhemangioendotheliomacurrent pages 2-5): Yi Ji, Siyuan Chen, Kaiying Yang, Chunchao Xia, and Li Li. Kaposiform hemangioendothelioma: current knowledge and future perspectives. Orphanet Journal of Rare Diseases, Feb 2020. URL: https://doi.org/10.1186/s13023-020-1320-1, doi:10.1186/s13023-020-1320-1. This article has 230 citations and is from a peer-reviewed journal.

  9. (ji2020kaposiformhemangioendotheliomacurrent pages 8-10): Yi Ji, Siyuan Chen, Kaiying Yang, Chunchao Xia, and Li Li. Kaposiform hemangioendothelioma: current knowledge and future perspectives. Orphanet Journal of Rare Diseases, Feb 2020. URL: https://doi.org/10.1186/s13023-020-1320-1, doi:10.1186/s13023-020-1320-1. This article has 230 citations and is from a peer-reviewed journal.

  10. (li2024treatmentexperiencefor pages 5-7): Miaomiao Li, Xusheng Wang, Rosalind Kieran, Zheng Wei Sun, Yubin Gong, Hongzhao Lei, Bin Sun, Li Xiao, Yanlin Wang, Song Wang, Zhiyu Li, Luying Wang, Renrong Lv, Feng Xue, Jianfeng Ge, Changxian Dong, and Ran Huo. Treatment experience for different risk groups of kaposiform hemangioendothelioma. Frontiers in Oncology, Jun 2024. URL: https://doi.org/10.3389/fonc.2024.1336763, doi:10.3389/fonc.2024.1336763. This article has 10 citations.

  11. (ji2020kaposiformhemangioendotheliomacurrent pages 10-12): Yi Ji, Siyuan Chen, Kaiying Yang, Chunchao Xia, and Li Li. Kaposiform hemangioendothelioma: current knowledge and future perspectives. Orphanet Journal of Rare Diseases, Feb 2020. URL: https://doi.org/10.1186/s13023-020-1320-1, doi:10.1186/s13023-020-1320-1. This article has 230 citations and is from a peer-reviewed journal.

  12. (NCT02110069 chunk 1): Denise Martin Adams. A Study to Compare Vincristine to Sirolimus for Treatment of High Risk Vascular Tumors. Boston Children's Hospital. 2017. ClinicalTrials.gov Identifier: NCT02110069

  13. (li2019localsutureligationassisted pages 1-2): Xiao Li, Ming‑Zhe Wen, Li‑Xin Su, Xi‑Tao Yang, Yi‑Feng Han, and Xin‑Dong Fan. Local suture ligation-assisted percutaneous sclerotherapy for kasabach-merritt phenomenon-associated kaposiform haemangioendothelioma. Oncology Letters, 17:981-989, Nov 2019. URL: https://doi.org/10.3892/ol.2018.9661, doi:10.3892/ol.2018.9661. This article has 5 citations and is from a peer-reviewed journal.

  14. (NCT04775173 chunk 1): Yi Ji. Efficacy and Safety of Different Concentrations of Sirolimus in the Treatment of Kaposiform Hemangioendothelioma.. West China Hospital. 2021. ClinicalTrials.gov Identifier: NCT04775173

  15. (ji2020kaposiformhemangioendotheliomacurrent pages 12-13): Yi Ji, Siyuan Chen, Kaiying Yang, Chunchao Xia, and Li Li. Kaposiform hemangioendothelioma: current knowledge and future perspectives. Orphanet Journal of Rare Diseases, Feb 2020. URL: https://doi.org/10.1186/s13023-020-1320-1, doi:10.1186/s13023-020-1320-1. This article has 230 citations and is from a peer-reviewed journal.

  16. (gasparella2025thevascernvascadiagnostic pages 1-2): Paolo Gasparella, Emir Q. Haxhija, Rune Andersen, Maria Barea, Eulalia Baselga, Miguel Bejarano Serrano, Sigurd Berger, Annouk Anne Bisdorff, Olivia Boccara, Petra Borgards, Maria Bom-Sucesso, Laurence M. Boon, Anca Maria Cimpean, Andrea Diociaiuti, Veronika Dvorakova, May El Hachem, Sofia Frisk, Nader Ghaffarpour, Annegret Holm, Alan D. Irvine, Mikkel Kaltoft, Friedrich G. Kapp, Olga Koskova, Kristiina Kyrklund, Miguel Madureira, Darius Palionis, Przemysław Przewratil, Bitten Schönewolf-Greulich, Maria-Corina Stanciulescu, Jaroslav Štěrba, Jukka Tolonen, Birute Vaisnyte, Carine van der Vleuten, Dariusz Wyrzykowski, Leo Schultze Kool, and Miikka Vikkula. The vascern-vasca diagnostic and management pathways for kaposiform hemangioendothelioma. European Journal of Pediatrics, Dec 2025. URL: https://doi.org/10.1007/s00431-025-06631-6, doi:10.1007/s00431-025-06631-6. This article has 5 citations and is from a peer-reviewed journal.

  17. (li2024treatmentexperiencefor pages 9-10): Miaomiao Li, Xusheng Wang, Rosalind Kieran, Zheng Wei Sun, Yubin Gong, Hongzhao Lei, Bin Sun, Li Xiao, Yanlin Wang, Song Wang, Zhiyu Li, Luying Wang, Renrong Lv, Feng Xue, Jianfeng Ge, Changxian Dong, and Ran Huo. Treatment experience for different risk groups of kaposiform hemangioendothelioma. Frontiers in Oncology, Jun 2024. URL: https://doi.org/10.3389/fonc.2024.1336763, doi:10.3389/fonc.2024.1336763. This article has 10 citations.

  18. (NCT04448873 chunk 1): Guided Discontinuation Versus Maintenance Treatment of Sirolimus in Pediatric Patients With Kaposiform Hemangioendothelioma. Children's Hospital of Fudan University. 2020. ClinicalTrials.gov Identifier: NCT04448873

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  • MONDO:0007708 (3 mentions) - the report calls it "if available"; MONDO calls it Kasabach-Merritt syndrome