Scott syndrome is an extremely rare autosomal recessive bleeding disorder caused by loss of ANO6 (anoctamin-6/TMEM16F), the calcium-dependent phospholipid scramblase of the platelet plasma membrane. It occupies a unique position among the inherited platelet disorders: the platelets adhere, activate, secrete and aggregate normally, so every routine platelet test can be unremarkable, and what fails is the last step before primary hemostasis hands off to coagulation. A strongly activated platelet normally scrambles its membrane phospholipids and externalizes phosphatidylserine, and the resulting negatively charged surface is where the tenase and prothrombinase complexes assemble and accelerate; without it, thrombin generation at the site of injury collapses even though the plasma coagulation factors are all present and normal. That is why the disorder was originally described in the language of coagulation - "prothrombin consumption deficiency", a defect of prothrombin conversion - decades before anyone knew a platelet membrane protein was responsible. It is also why the disorder is a genuine diagnostic trap: an isolated defect of platelet procoagulant activity is invisible to aggregometry, invisible to platelet counts and morphology, and invisible to standard clotting screens performed on plasma. Only a handful of patients have ever been described.
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Conditions with similar clinical presentations that must be differentiated from Scott Syndrome:
name: Scott Syndrome
creation_date: "2026-08-24T00:00:00Z"
category: Mendelian
parents:
- Inherited Platelet Disorder
- Bleeding Disorder
disease_term:
preferred_term: Scott syndrome
term:
id: MONDO:0009885
label: Scott syndrome
synonyms:
- SCTS
- BDPLT7
- bleeding disorder, platelet-type, 7
- platelet factor X receptor deficiency
- familial prothrombin consumption deficiency
description: >-
Scott syndrome is an extremely rare autosomal recessive bleeding disorder
caused by loss of ANO6 (anoctamin-6/TMEM16F), the calcium-dependent
phospholipid scramblase of the platelet plasma membrane. It occupies a unique
position among the inherited platelet disorders: the platelets adhere,
activate, secrete and aggregate normally, so every routine platelet test can
be unremarkable, and what fails is the last step before primary hemostasis
hands off to coagulation. A strongly activated platelet normally scrambles its
membrane phospholipids and externalizes phosphatidylserine, and the resulting
negatively charged surface is where the tenase and prothrombinase complexes
assemble and accelerate; without it, thrombin generation at the site of injury
collapses even though the plasma coagulation factors are all present and
normal.
That is why the disorder was originally described in the language of
coagulation - "prothrombin consumption deficiency", a defect of prothrombin
conversion - decades before anyone knew a platelet membrane protein was
responsible. It is also why the disorder is a genuine diagnostic trap: an
isolated defect of platelet procoagulant activity is invisible to
aggregometry, invisible to platelet counts and morphology, and invisible to
standard clotting screens performed on plasma. Only a handful of patients have
ever been described.
pathophysiology:
- name: Biallelic Loss of Function in ANO6
role: trigger
biological_scale: MOLECULAR
conforms_to: "primary_hemostatic_plug_failure#Loss of a Platelet Primary-Hemostatic Component"
description: >-
Loss-of-function variants in ANO6, encoding TMEM16F/anoctamin-6, cause the
disease. The index patient carried a splice-acceptor-site variant causing
premature termination of the protein. TMEM16F is a plasma-membrane protein
with eight transmembrane segments; its identification in 2010 by expression
cloning ended a search for the platelet scramblase that had run since the
activity was biochemically characterized in the 1980s.
genetic_context:
variant_origin: GERMLINE
functional_impact_category: LOSS_OF_FUNCTION
cell_types:
- preferred_term: platelet
term:
id: CL:0000233
label: platelet
evidence:
- reference: PMID:21107324
reference_title: Calcium-dependent phospholipid scrambling by TMEM16F.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "A patient with Scott syndrome, which results from a defect in phospholipid scrambling activity, was found to carry a mutation at a splice-acceptor site of the gene encoding TMEM16F, causing the premature termination of the protein."
explanation: >-
Establishes the causal gene and the specific allele class of the index
patient.
- reference: PMID:21958383
reference_title: "Platelet membrane phospholipid asymmetry: from the characterization of a scramblase activity to the identification of an essential protein mutated in Scott syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a significant advance has recently been made with the identification of TMEM16F, a membrane protein essential for calcium-dependent PS exposure whose loss of function mutations are found in Scott syndrome"
explanation: >-
Independent confirmation that loss-of-function variants in this gene are
the cause, and places the discovery in its historical context.
downstream:
- target: Loss of Calcium-Dependent Phospholipid Scrambling
causal_link_type: DIRECT
description: >-
TMEM16F is the essential component of the calcium-dependent scrambling
activity, so losing it removes the activity.
- name: Loss of Calcium-Dependent Phospholipid Scrambling
role: central_effector
biological_scale: MOLECULAR
conforms_to: "primary_hemostatic_plug_failure#Impaired Platelet Procoagulant Membrane Response"
description: >-
The rate-limiting lesion. Resting cells maintain phospholipid asymmetry
using ATP-dependent translocases (flippases and floppases) that move
phospholipids unidirectionally against a gradient; on activation an
energy-independent, calcium-dependent scramblase instead exchanges
phospholipids bidirectionally between the two leaflets, collapsing the
asymmetry and exposing phosphatidylserine. It is this second, scramblase
activity that is lost here - the translocases are unaffected - so the defect
is specific to the activated state, which is why resting platelets are
entirely normal.
cell_types:
- preferred_term: platelet
term:
id: CL:0000233
label: platelet
biological_processes:
- preferred_term: calcium-dependent phosphatidylserine externalization
term:
id: GO:0017121
label: plasma membrane phospholipid scrambling
modifier: LOSS_OF_FUNCTION
evidence:
- reference: PMID:21958383
reference_title: "Platelet membrane phospholipid asymmetry: from the characterization of a scramblase activity to the identification of an essential protein mutated in Scott syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "They also use an energy-independent, calcium-dependent scramblase activity to govern the bidirectional exchange of phospholipids between the two leaflets of the bilayer; this activity is essential for PS exposure during platelet activation. Scramblase activity, biochemically characterized in the 1980s, is deficient in patients with Scott syndrome, a rare inherited bleeding disorder with defective platelet procoagulant activity."
explanation: >-
Distinguishes the scramblase activity from the ATP-dependent translocases
and states that it is the one deficient in this disorder - the exact
claim this node makes.
- reference: PMID:21107324
reference_title: Calcium-dependent phospholipid scrambling by TMEM16F.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Wild-type TMEM16F was localized on the plasma membrane and conferred Ca(2+)-dependent scrambling of phospholipids."
explanation: >-
Direct demonstration that the protein confers the activity this node
describes as lost.
downstream:
- target: Failure of Platelet Procoagulant Surface Formation
causal_link_type: DIRECT
description: >-
No scrambling means no phosphatidylserine on the outer leaflet.
- name: Failure of Platelet Procoagulant Surface Formation
role: effector
biological_scale: CELLULAR
description: >-
The activated platelet fails to present the anionic surface that
coagulation depends on, and fails to shed the phosphatidylserine-bearing
microparticles that extend that surface into the surrounding plasma. Binding
of the clotting enzyme complexes to a negatively charged membrane surface is
what allows the dramatic acceleration of zymogen-to-protease conversion, so
the loss is quantitative in the most consequential sense: the reactions
still occur, but far too slowly.
cell_types:
- preferred_term: platelet
term:
id: CL:0000233
label: platelet
biological_processes:
- preferred_term: platelet procoagulant activity
term:
id: GO:0007596
label: blood coagulation
modifier: DECREASED
evidence:
- reference: PMID:21958383
reference_title: "Platelet membrane phospholipid asymmetry: from the characterization of a scramblase activity to the identification of an essential protein mutated in Scott syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This newly-exposed PS surface is a major component of normal hemostasis because it supports platelet procoagulant function."
explanation: >-
States that the exposed surface is what supports procoagulant function,
which is what this node records as failing.
downstream:
- target: Impaired Local Thrombin Burst
causal_link_type: DIRECT
description: >-
The tenase and prothrombinase complexes lose the surface on which they
assemble and accelerate.
- name: Impaired Local Thrombin Burst
role: effector
biological_scale: TISSUE
description: >-
Without surface-accelerated assembly of the clotting enzyme complexes there
is no burst of thrombin at the site of injury, so fibrin formation and the
further platelet activation that thrombin drives both fail. Plasma
coagulation factor levels are normal throughout - the defect is in where the
reactions happen, not in what is available to run them - which is why
standard plasma-based clotting assays are normal and why the historical name
for the disorder was framed as defective prothrombin consumption.
biological_processes:
- preferred_term: blood coagulation
term:
id: GO:0007596
label: blood coagulation
modifier: DECREASED
evidence:
- reference: PMID:21958383
reference_title: "Platelet membrane phospholipid asymmetry: from the characterization of a scramblase activity to the identification of an essential protein mutated in Scott syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Binding of blood clotting enzyme complexes to this negatively-charged membrane surface allows a dramatic increase in the rate of conversion of zymogens to active serine proteases, which in turn produce a burst of thrombin leading to the formation of a fibrin clot and further platelet activation."
explanation: >-
Sets out the surface-dependent acceleration and the thrombin burst whose
loss this node represents, including the downstream fibrin and
platelet-activation consequences.
downstream:
- target: Failure of Primary Hemostatic Plug Formation
causal_link_type: DIRECT
description: >-
The platelet plug is not consolidated by fibrin and remains mechanically
inadequate.
- name: Failure of Primary Hemostatic Plug Formation
role: effector
biological_scale: TISSUE
conforms_to: "primary_hemostatic_plug_failure#Failure of Primary Hemostatic Plug Formation"
description: >-
Reached by an unusual route - not by failing to build the platelet mass, but
by failing to consolidate it. The distinctive clinical consequence is that
bleeding tends to be delayed and to follow trauma or surgery rather than
arising spontaneously, since the initial platelet plug forms normally and
then fails to hold.
biological_processes:
- preferred_term: primary hemostasis
term:
id: GO:0007599
label: hemostasis
modifier: DECREASED
evidence:
- reference: PMID:21781244
reference_title: Advances in our understanding of the molecular basis of disorders of platelet function.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A mutation in transmembrane protein 16F (TMEM16F) has been linked to a defective procoagulant activity and phosphatidylserine expression in the Scott syndrome."
explanation: >-
Places this disorder within the family of platelet function defects that
converge on failure of the platelet's haemostatic role.
downstream:
- target: Bleeding Diathesis
causal_link_type: DIRECT
description: Failure of platelet-supported haemostasis at the site of injury.
- name: Bleeding Diathesis
role: consequence
biological_scale: ORGANISM
conforms_to: "primary_hemostatic_plug_failure#Mucocutaneous Bleeding Diathesis"
description: >-
A haemostatically significant bleeding tendency, established in patients by
prolonged bleeding time. The phenotype is deliberately named "bleeding
diathesis" rather than "mucocutaneous bleeding" here: with only a handful of
patients ever described, the site distribution characteristic of the wider
family is not independently established for this disorder, and asserting it
would be extrapolation from the module rather than a curated observation.
biological_processes:
- preferred_term: primary hemostasis
term:
id: GO:0007599
label: hemostasis
modifier: DECREASED
evidence:
- reference: PMID:21958383
reference_title: "Platelet membrane phospholipid asymmetry: from the characterization of a scramblase activity to the identification of an essential protein mutated in Scott syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Scramblase activity, biochemically characterized in the 1980s, is deficient in patients with Scott syndrome, a rare inherited bleeding disorder with defective platelet procoagulant activity."
explanation: >-
Human evidence that the disorder is a bleeding disorder in patients. Added
so this node is not supported by model-organism evidence alone, which the
evidence policy warns against for a human phenotype.
- reference: PMID:26481309
reference_title: "Survival protein anoctamin-6 controls multiple platelet responses including phospholipid scrambling, swelling, and protein cleavage."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "mouse deficiency of Ano6 but not of other channels affects viability and phenocopies the complex changes in platelets from hemostatically impaired patients with Scott syndrome"
explanation: >-
Corroborates the bleeding phenotype indirectly, and characterizes the
patients as hemostatically impaired. Tagged MODEL_ORGANISM rather than
HUMAN_CLINICAL because the result the sentence reports is the mouse
phenocopy; the human clause is its premise, not its finding.
phenotypes:
- category: Hematologic
name: Defective Platelet Phosphatidylserine Exposure
description: >-
The defining laboratory abnormality, and the only one that reliably
identifies the disorder: on strong activation, patient platelets fail to
externalize phosphatidylserine and fail to shed procoagulant microparticles.
Routine aggregometry does not detect it.
phenotype_term:
preferred_term: Abnormal platelet function
term:
id: HP:0011869
label: Abnormal platelet function
frequency: OBLIGATE
evidence:
- reference: PMID:26481309
reference_title: "Survival protein anoctamin-6 controls multiple platelet responses including phospholipid scrambling, swelling, and protein cleavage."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Scott syndrome is a rare bleeding disorder, characterized by altered Ca(2+)-dependent platelet signaling with defective phosphatidylserine (PS) exposure and microparticle formation, and is linked to mutations in the ANO6 gene, encoding anoctamin (Ano)6."
explanation: >-
States the defining defect - phosphatidylserine exposure and microparticle
formation - supporting the OBLIGATE frequency, since it is what defines the
diagnosis. The bound HP term is the generic parent because the HPO has no
term for platelet procoagulant/phosphatidylserine-exposure defects.
- category: Hematologic
name: Preserved Platelet Aggregation
description: >-
A negative finding curated deliberately, because it is diagnostically
decisive: collagen-induced aggregate formation is normal in patient
platelets. This is the feature that separates the disorder from every other
member of the family and the reason it is missed by a standard platelet
function workup.
phenotype_term:
preferred_term: Preserved collagen-induced platelet aggregation
notes: >-
Deliberately carries NO `term:`. The HPO has no class for a preserved or
normal platelet function finding, and the nearest candidate
(`HP:0011869 Abnormal platelet function`) asserts the exact opposite of what
is curated here - a downstream consumer reading only the bound term would
get the reverse claim about the one feature that distinguishes this disorder
from every other member of its family. Per the ontology contract, no term
beats a misleading one. A new-term request for a normal/preserved platelet
aggregation finding would be the durable fix.
evidence:
- reference: PMID:26481309
reference_title: "Survival protein anoctamin-6 controls multiple platelet responses including phospholipid scrambling, swelling, and protein cleavage."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "1) normal collagen-induced aggregate formation (P > 0.05) with reduced PS exposure (-65 to 90%)"
explanation: >-
Reports normal collagen-induced aggregation alongside reduced
phosphatidylserine exposure. MODEL_ORGANISM because the quantified figures
are from Ano6-deficient mice, presented in the source as phenocopying the
patient platelets studied alongside them.
- category: Hematologic
name: Prolonged Bleeding Time
phenotype_term:
preferred_term: Prolonged bleeding time
term:
id: HP:0003010
label: Prolonged bleeding time
evidence:
- reference: PMID:26481309
reference_title: "Survival protein anoctamin-6 controls multiple platelet responses including phospholipid scrambling, swelling, and protein cleavage."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In 2 mouse strains, deficiency in Ano6 resulted in reduced viability with increased bleeding time to 28.6 min (control 6.4 min, P < 0.05)."
explanation: >-
PARTIAL because the quantified bleeding-time prolongation is measured in
the mouse; the corresponding human observation is asserted in the same
source only as hemostatic impairment, without a figure.
genetic:
- name: ANO6
gene_term:
preferred_term: ANO6
term:
id: hgnc:25240
label: ANO6
relationship_type: CAUSATIVE
notes: >-
Encodes TMEM16F/anoctamin-6. Loss-of-function variants cause the disorder;
the index patient's allele was a splice-acceptor-site variant producing
premature termination. The specificity of the gene assignment is unusually
well controlled: mice deficient in the related anoctamin ANO1, or in the
calcium-dependent KCa3.1 Gardos channel, showed no reduction in platelet
responses, so the phenotype is attributable to ANO6 rather than to the
anoctamin family or to calcium-activated channels generally.
evidence:
- reference: PMID:26481309
reference_title: "Survival protein anoctamin-6 controls multiple platelet responses including phospholipid scrambling, swelling, and protein cleavage."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Deficiency in Ano1 or Gardos channel did not reduce platelet responses compared with control mice (P > 0.1)."
explanation: >-
The negative controls that establish the specificity of the ANO6
assignment asserted in this gene block.
inheritance:
- name: Autosomal Recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Biallelic ANO6 loss of function. Recorded in MONDO and OMIM as autosomal
recessive; the number of reported patients is too small to support any
statement about carrier phenotype.
evidence:
- reference: PMID:21107324
reference_title: Calcium-dependent phospholipid scrambling by TMEM16F.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "A patient with Scott syndrome, which results from a defect in phospholipid scrambling activity, was found to carry a mutation at a splice-acceptor site of the gene encoding TMEM16F"
explanation: >-
PARTIAL - documents a loss-of-function allele in a patient but does not
itself state the mode of inheritance, which is taken from OMIM/MONDO.
animal_models:
- name: Ano6-deficient mouse
species: Mouse
genotype: Ano6 knockout (homozygous and heterozygous deficiency)
publication: PMID:26481309
description: >-
The model that established the disorder's platelet phenotype as
ANO6-specific. Ano6-deficient mice reproduce the full complex of patient
platelet changes - normal aggregation with markedly reduced
phosphatidylserine exposure, reduced calcium-dependent swelling and membrane
blebbing, and reduced calpain-dependent protein cleavage - while mice
deficient in ANO1 or the Gardos channel do not. It also reveals that ANO6
does more than scramble lipids, which is why the disorder's phenotype may be
broader than the scramblase account alone predicts.
modeled_mechanisms:
- target: Loss of Calcium-Dependent Phospholipid Scrambling
relationship: RECAPITULATES
fidelity: HIGH
description: >-
Reproduces the reduced phosphatidylserine exposure of patient platelets,
with the ANO1 and Gardos-channel knockouts serving as specificity controls.
limitations: >-
Ano6 deficiency also reduces murine viability, which has no counterpart in
the surviving patients, so the mouse is more severely affected than the
human disorder. The additional murine phenotypes (swelling, blebbing,
calpain-dependent cleavage) are reported as phenocopying the patient
platelets but are not separately established as clinical features.
readouts:
- name: Calcium-induced platelet phosphatidylserine exposure
target: Loss of Calcium-Dependent Phospholipid Scrambling
direction: DECREASED
interpretation: >-
Direct functional correlate of the human scramblase deficiency.
evidence:
- reference: PMID:26481309
reference_title: "Survival protein anoctamin-6 controls multiple platelet responses including phospholipid scrambling, swelling, and protein cleavage."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "1) normal collagen-induced aggregate formation (P > 0.05) with reduced PS exposure (-65 to 90%); 2) lowered Ca(2+)-dependent swelling (-80%) and membrane blebbing (-90%); 3) reduced calpain-dependent protein cleavage (-60%)"
explanation: >-
Reports the quantified reduction in phosphatidylserine exposure
together with the accompanying membrane responses.
evidence:
- reference: PMID:26481309
reference_title: "Survival protein anoctamin-6 controls multiple platelet responses including phospholipid scrambling, swelling, and protein cleavage."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Platelets from these mice were extensively analyzed on molecular functions and compared with platelets from a patient with Scott syndrome."
explanation: >-
The direct patient-versus-model comparison that makes this model
informative for the human node.
diagnosis:
- name: Platelet Procoagulant Activity Testing
description: >-
The disorder cannot be diagnosed by the tests usually ordered for a bleeding
patient. Platelet count, morphology, aggregometry and plasma coagulation
screens are all normal or near-normal; the diagnosis requires direct
measurement of activation-dependent phosphatidylserine exposure (for
instance annexin V binding by flow cytometry) or of platelet procoagulant
activity and microparticle generation, followed by ANO6 sequencing.
evidence:
- reference: PMID:26481309
reference_title: "Survival protein anoctamin-6 controls multiple platelet responses including phospholipid scrambling, swelling, and protein cleavage."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Scott syndrome is a rare bleeding disorder, characterized by altered Ca(2+)-dependent platelet signaling with defective phosphatidylserine (PS) exposure and microparticle formation"
explanation: >-
Names the two measurements on which the diagnosis rests.
differential_diagnoses:
- name: Coagulation Factor Deficiencies
description: >-
The historical confusion, and still the natural first thought: the
phenotype is one of impaired thrombin generation with a normal platelet
count and normal aggregation, which is what a factor deficiency looks like.
Excluded by normal plasma factor assays - the defect is in the surface, not
in the factors.
evidence:
- reference: PMID:21958383
reference_title: "Platelet membrane phospholipid asymmetry: from the characterization of a scramblase activity to the identification of an essential protein mutated in Scott syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Scramblase activity, biochemically characterized in the 1980s, is deficient in patients with Scott syndrome, a rare inherited bleeding disorder with defective platelet procoagulant activity."
explanation: >-
Locates the defect in platelet procoagulant activity rather than in the
plasma coagulation factors, which is the discriminator.
- name: Other Inherited Platelet Function Disorders
description: >-
Bernard-Soulier syndrome, Glanzmann thrombasthenia, the storage pool
diseases and the agonist-receptor defects all produce abnormal aggregometry.
This disorder does not - preserved aggregation with a genuine bleeding
tendency is the discriminating combination.
evidence:
- reference: PMID:26481309
reference_title: "Survival protein anoctamin-6 controls multiple platelet responses including phospholipid scrambling, swelling, and protein cleavage."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "normal collagen-induced aggregate formation (P > 0.05) with reduced PS exposure"
explanation: >-
Documents the preserved-aggregation/reduced-exposure combination that
distinguishes this disorder from the rest of the family.
discussions:
- discussion_id: gap_ano6_beyond_scrambling
kind: KNOWLEDGE_GAP
prompt: >-
Is the bleeding phenotype of ANO6 deficiency fully explained by loss of
phosphatidylserine scrambling, or do the other ANO6-dependent platelet
responses contribute?
attaches_to:
- pathophysiology#Loss of Calcium-Dependent Phospholipid Scrambling
- pathophysiology#Failure of Platelet Procoagulant Surface Formation
rationale: >-
The disorder is conventionally described, and is curated here, as a
scramblase deficiency. But ANO6-deficient platelets also show markedly
reduced calcium-dependent swelling and membrane blebbing and reduced
calpain-dependent protein cleavage, and these are not obviously downstream of
scrambling - the source frames ANO6 as controlling multiple platelet
responses, plural. Since membrane blebbing is how procoagulant
microparticles are shed, at least one of these could contribute
independently to the haemostatic defect. Resolving this matters for whether
a therapy aimed at restoring phosphatidylserine exposure alone would be
sufficient.
proposed_experiments:
- experiment_id: exp_ano6_separation_of_function
name: Separation-of-function ANO6 variants in patient-derived megakaryocytes
description: >-
Express ANO6 variants that dissociate scrambling from ion-channel and
blebbing activity in ANO6-null iPSC-derived megakaryocytes, and measure
phosphatidylserine exposure, microparticle release and thrombin generation
independently. Rescue of thrombin generation by a scrambling-only variant
would settle the question in favour of the conventional account.
evidence:
- reference: PMID:26481309
reference_title: "Survival protein anoctamin-6 controls multiple platelet responses including phospholipid scrambling, swelling, and protein cleavage."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We investigated how the complex platelet phenotype of this syndrome is linked to defective expression of Anos or other ion channels."
explanation: >-
The source frames the platelet phenotype as complex and its attribution as
an open investigation, which is the basis of this gap.
notes: >-
Conformance: this entry is the worked conformer for the PROCOAGULANT arm of
`primary_hemostatic_plug_failure` - `#Impaired Platelet Procoagulant Membrane
Response` - which the module describes as its narrowest arm and gates on
phosphatidylserine-exposure or procoagulant-activity evidence rather than on a
clotting abnormality. That gate is met here directly. The entry does NOT
conform to the adhesion, secretion or aggregation arms: aggregation is
explicitly preserved, and curating it at any of those would be false.
Rarity and its consequences for this entry. Only a handful of patients have
ever been reported, which constrains what can honestly be curated. No
prevalence record is included - there is no denominator anywhere in the
literature. The consequence node is named `Bleeding Diathesis` rather than
`Mucocutaneous Bleeding Diathesis`, because the site distribution
characteristic of the wider disorder family has not been established
separately for this disorder and importing it from the module would be
extrapolation. Several quantified statements about platelet behaviour come
from the Ano6-deficient mouse and are marked MODEL_ORGANISM even where the
source presents them as phenocopying the patient, so the model dependency is
visible rather than buried.
Historical naming. The synonyms preserve the coagulation-era names
("prothrombin consumption deficiency", "platelet factor X receptor
deficiency") because they are how the disorder appears in older literature and
in some registries, and because they record something true about the
mechanism - the phenotype really is one of defective thrombin generation,
arrived at through a platelet membrane defect.
No `treatments:` block, deliberately. Management of bleeding in this disorder
is not addressed by any source in this repository's reference cache - the
three cited papers are a scramblase-identification study, a membrane-biology
review and a mouse-model paper, and none names an agent or regimen for
patients. The disorder's mechanism does predict something clinically
important - because the defect is a failure of platelet-supported thrombin
generation rather than of platelet number or aggregation, platelet
transfusion supplies competent platelets and is the rational intervention -
but that is an inference from mechanism, not a curated finding, so it is
stated here rather than curated as an evidenced treatment. This entry also
does NOT inherit the module's rFVIIa pattern; `primary_hemostatic_plug_failure`
states that its treatment is a mechanistic target pattern evidenced in
Glanzmann thrombasthenia and is not inherited by conformers.
Curation provenance. This entry was curated by direct review of the cached
full text and abstracts of the references listed in `references:`, not from a
deep-research provider artifact, so there is no corresponding file under
`research/`. Candidate PMIDs were located by PubMed search and each was
fetched with `just fetch-reference` before use; several initially plausible
identifiers turned out to be unrelated papers and were discarded rather than
cited on their titles. Every snippet in this entry is an exact substring of
the cached reference text.
references:
- reference: PMID:21107324
title: "Calcium-dependent phospholipid scrambling by TMEM16F."
- reference: PMID:21958383
title: "Platelet membrane phospholipid asymmetry: from the characterization of a scramblase activity to the identification of an essential protein mutated in Scott syndrome."
- reference: PMID:26481309
title: "Survival protein anoctamin-6 controls multiple platelet responses including phospholipid scrambling, swelling, and protein cleavage."
- reference: PMID:21781244
title: "Advances in our understanding of the molecular basis of disorders of platelet function."