| Category | Key points | Quantitative data | Key citations |
|---|---|---|---|
| Disease name / synonyms | Hereditary combined vitamin K-dependent coagulation factor deficiency (VKCFD); inherited vitamin K-dependent coagulation factors deficiency; vitamin K-dependent clotting factor deficiency; VKCFD type 1 (GGCX-related) and type 2 (VKORC1-related); part of familial multiple coagulation factor deficiencies | ~50 affected families reported in 2025 review; historically <30 kindreds worldwide in earlier literature | (pqac-00000002, pqac-00000003, pqac-00000054, pqac-00000056) |
| Inheritance | Mendelian, autosomal recessive; variable expressivity; homozygous variants common, especially in consanguineous families | Sex ratio reported 1:1; homozygous variants account for >50% of reported cases in one recent review | (pqac-00000007, pqac-00000052, pqac-00000054) |
| Causal genes | **GGCX** (gamma-glutamyl carboxylase) causes VKCFD1; **VKORC1** (vitamin K epoxide reductase complex subunit 1) causes VKCFD2 | GGCX OMIM **137167**; VKORC1 OMIM **608547**; disease subtype labels: VKCFD1 and VKCFD2 | (pqac-00000002, pqac-00000003, pqac-00000013) |
| Molecular defect | Defective vitamin K cycle / γ-carboxylation causes undercarboxylated VK-dependent proteins (PIVKA) with low activity of factors II, VII, IX, X and proteins C/S/Z; extrahepatic VKD proteins explain skeletal/PXE-like phenotypes | Gla residues are required for Ca2+ binding; PIVKA-II/DCP is a sensitive indirect biomarker | (pqac-00000008, pqac-00000009, pqac-00000012, pqac-00000015) |
| Variant spectrum / recurrent variants | GGCX variants are mostly missense but include deletions and splice variants; VKORC1 recurrent **c.292C>T (p.Arg98Trp, R98W)** reported in multiple unrelated families; genotype influences vitamin K responsiveness | At least **34-40** GGCX mutations reported; VKORC1 R98W reported in **3 unrelated families** in earlier literature | (pqac-00000004, pqac-00000005, pqac-00000010, pqac-00000014, pqac-00000050, pqac-00000051, pqac-00000054) |
| Key clinical features | Bleeding spectrum from mild mucocutaneous bleeding to life-threatening neonatal hemorrhage; umbilical stump bleeding, epistaxis, GI bleeding, postoperative bleeding; rare hemarthrosis; GGCX-related disease can include skeletal/cardiac/PXE-like findings | In 61-patient review: **74%** bled overall; among bleeding patients **60%** mucocutaneous, **26%** surgery/antibiotic-associated; umbilical cord bleeding in **3 neonates** | (pqac-00000016, pqac-00000017, pqac-00000020, pqac-00000021) |
| Severe outcomes / onset | Severe disease often presents in neonatal period or infancy; intracranial hemorrhage is a major early-life risk; later-onset milder phenotypes also occur | Intracranial hemorrhage **27% overall**; **92%** of intracranial hemorrhages occurred before age 1; among 33 VKCFD1 patients, **10** had severe onset before age 1 | (pqac-00000016, pqac-00000019, pqac-00000020) |
| Non-hemorrhagic phenotypes | Extrahemostatic features are much more prominent in GGCX-related disease: Keutel-like skeletal/cardiac disease, reduced bone mass, midface hypoplasia, chondrodysplasia punctata, skin laxity/PXE-like skin and ocular findings, subclinical atherosclerosis | In 61-patient review: non-hemorrhagic features in **55%** of GGCX cases and **0%** of VKORC1 cases; Keutel-like syndrome **31%**; PXE-like features **8%**; subclinical atherosclerosis **38%** | (pqac-00000016, pqac-00000019, pqac-00000022, pqac-00000053) |
| Routine coagulation screening | Hallmark pattern is prolonged PT/INR with prolonged or variably prolonged aPTT; PT often more prolonged because factor VII has the shortest half-life | Example values: INR **3.63** with aPTT **37 s**; another case had aPTT **57 s** and nondetectable PT/INR | (pqac-00000024, pqac-00000028, pqac-00000029) |
| Mixing study / factor assays | 50:50 mixing study typically corrects PT and aPTT, supporting factor deficiency rather than inhibitor; factor assays show low VK-dependent factors with normal FV, fibrinogen, platelets | Factor activities often **20-60%**, less commonly **<10%**; reported ranges: FII **2%-normal**, FVII **<1%-normal**, FIX **4%-normal**, FX **2%-33%** | (pqac-00000024, pqac-00000026, pqac-00000027, pqac-00000023) |
| Example diagnostic factor pattern | Typical inherited VKCFD pattern is low FII/FVII/FIX/FX, relatively preserved FV, normal fibrinogen/platelets; acquired causes should be excluded by vitamin K level/history | Example: FII **30%**, FVII **1%**, FIX **6%**, FX **9%**, FV **90%**, vitamin K **2.2 ng/mL** (normal); another case: FII **17%**, FVII **2.9%**, FIX **11%**, FX **8.5%** | (pqac-00000025, pqac-00000029) |
| Biomarkers / differential diagnosis | PIVKA-II (DCP) rises early and is sensitive but not specific; plasma vitamin K1 by HPLC can help identify acquired deficiency; distinction from acquired VK deficiency rests on history, liver disease/malabsorption evaluation, transient VK response, and molecular testing | Plasma VK1 **<0.15 μg/L** suggests deficiency in non-fasting individuals; neonatal PIVKA-II can be **>10 ng/mL** in VK deficiency; FII/FIIE ratio **<0.86** and FIIE−FII **≥0.045 U/mL** support VK-related reduced carboxylation | (pqac-00000026, pqac-00000027, pqac-00000030, pqac-00000031) |
| Epidemiology | Ultra-rare disease with broad geographic distribution and no strong ethnic predisposition, but more frequent in consanguineous populations | About **30 families** described worldwide in one review; France prevalence estimate **~1 per 1,000,000** | (pqac-00000049, pqac-00000052, pqac-00000054, pqac-00000056) |
| First-line treatment: vitamin K | Mainstay therapy is vitamin K1 (phylloquinone); oral prophylaxis often used chronically; IV vitamin K for poor responders or acute correction; response may be incomplete or mutation-dependent | Minor bleeding: **5-20 mg** IV or PO; chronic prophylaxis: **5-20 mg/day** PO **2-3 times weekly**; historical regimen **10 mg** PO **2-3 times weekly**; poor responders may need IV **5-20 mg/week** | (pqac-00000032, pqac-00000033, pqac-00000036, pqac-00000038) |
| Adjunct / replacement therapy | Tranexamic acid for mucosal bleeding/minor procedures; FFP or PCC for major bleeding or surgery; rFVIIa for life-threatening bleeding or difficult surgical settings | Tranexamic acid **1 g q6h** or **15-20 mL/kg**; FFP **15-20 mL/kg**; PCC **20-30 U/kg** (or **50-100 U/kg** in some acute VKD settings); rFVIIa **10-20 μg/kg IV** | (pqac-00000032, pqac-00000033, pqac-00000034, pqac-00000035) |
| Prevention / prognosis | Maternal vitamin K in late pregnancy may reduce neonatal bleeding risk in affected pregnancies; standard newborn vitamin K prophylaxis remains important. Prognosis is generally good with recognition and treatment, but neonatal ICH can be fatal and major surgery remains challenging | Third-trimester maternal VK1 supplementation recommended in at-risk pregnancies; oral neonatal prophylaxis may fail in malabsorption disorders | (pqac-00000033, pqac-00000034, pqac-00000035, pqac-00000038) |


*Table: This table condenses the main disease-defining features of hereditary vitamin K-dependent coagulation factor deficiency, including genetics, phenotype frequencies, diagnostics, epidemiology, and current treatment dosing. It is designed as a quick-reference artifact for a disease knowledge base entry.*