Inherited disorders of blood coagulation

Figures & data

Figure 1. Overview of the in-vivo blood coagulation cascade.

Figure 2. Classification of bleeding disorders. Von Willebrand disease (VWD) is primarily a disorder of ‘primary hemostasis’ (affecting platelet adhesion and aggregation), but as von Willebrand factor (VWF) can also contribute to ‘secondary hemostasis’ by providing factor VIII to sites of injury, VWD can also express clinical symptoms associated with failure of the coagulation cascade.

Table I. The coagulation factors.

Number	Name	Synthesis	Function
I	Fibrinogen	Liver	Precursor of fibrin, which stabilizes the soft plug
II	Prothrombin	Liver	Precursor of thrombin catalyzes the conversion of fibrinogen into fibrin. It also activates factors V, VIII, XI, XIII, and binds to thrombomodulin to activate protein C
III	Tissue factor, tissue thromboplastin	Endothelial cells	Contained within perivascular fibroblasts, boundary epithelial cells, and platelet-derived microparticles, binds to FVII to form a complex that triggers blood coagulation in vivo
IV	Calcium		Mediates the binding of terminal gamma-carboxy residues of coagulation factors to the phospholipid surfaces of the platelets
V	Proaccelerin, labile factor	Platelets (α granules), liver	Co-factor for FXa in prothrombinase complex that activates prothrombin to thrombin
VII	Proconvertin, stable factor	Liver	Binds to tissue factor and forms the enzymatic complex that initiates blood coagulation by activating factors X and IX
VIII	Antihemophilic factor A	Endothelial cells, liver	Co-factor of FIXa in the tenase complex that activates factor X
IX	Antihemophilic factor B, Christmas factor	Liver	Forms with FVIIIa the tenase complex, which activates factor X
X	Stuart–Prower factor	Liver	Binds with FVa to form a complex which cleaves prothrombin to thrombin
XI	Antihemophilic factor C, plasma thromboplastin antecedent	Liver	Is activated to factor XIa, which activates factor IX in a reaction requiring Ca^2+ ions
XII	Hageman factor	Liver	Activates prekallikrein and factor XI, triggering the intrinsic coagulation pathway (in vitro)
XIII	Fibrin stabilizing factor	Liver	Activated by thrombin, catalyzes formation of peptide bonds between adjacent fibrin monomers, thereby stabilizing the fibrin clot
	Prekallikrein, Fletcher factor	Endothelial cells	Activated to kallikrein by factor XIIa, catalyzes the further activation of factor XII to factor XIIa
	High-molecular-weight kininogen, Fitzgerald factor	Liver, endothelial cells	Circulates as a bimolecular complex with prekallikrein
	von Willebrand factor	Endothelial cells and megakaryocytes	Binds to and stabilizes FVIII in blood, mediates platelet aggregation

Table II. Platelet disorders.

Congenital

Thrombocytopenias:

MYH9-related platelet disorders

Congenital amegakaryocytic thrombocytopenia

Thrombocytopenia associated with skeletal defects

X-linked thrombocytopenia with dyserythropoiesis

Thrombocytopenia with predisposition to leukemia

Montreal platelet syndrome

Mediterranean macrothrombocytopenia

Disorders of platelet function:

Glanzmann thromboasthenia

Bernard–Soulier syndrome

Wiskott–Aldrich syndrome

Disorders of agonist platelet receptors and signal transduction

Disorders of platelet granules (e.g. δ-storage pool disease, α-storage pool disease

Other platelet disorders:

Scott syndrome

Acquired

Thrombocytopenias:

Aplastic anemia

Bone-marrow infiltrates (e.g. cancer)

Ionizing radiation and other causes of myelosuppression

Drugs (trimethoprim-sulfamethoxazole, gold, thiazide diuretics, estrogens, interferons)

Deficiency of vitamins and other essential trace elements or nutrients (e.g. vitamin B12, folate)

Viral infections

Disseminated intravascular coagulation (DIC)

Thrombotic thrombocytopenic purpura (TTP)

Idiopathic thrombocytopenia purpura (ITP)

Hemolytic-uremic syndrome

Hypersplenism and platelet sequestration

Acute hemorrhage

Hemoperfusion

Disorders of platelet function:

Chronic myelogenous leukemia

Myelofibrosis

Polycythemia vera

Primary thrombocythemia

Kidney failure

Multiple myeloma

Drugs (e.g. aspirin and other anti-inflammatory drugs, penicillins, phenothiazines, and prednisone)

Table III. Von Willebrand disease diagnosis and treatment.

VWD type	Laboratory features	Relative frequency	Treatment options^a
1	Low levels of functionally normal VWF. Ratios of VWF:CB/VWF:Ag and VWF:RCo/VWF:Ag are normal (above 0.7). FVIII levels also fall concordantly with VWF	Most frequent (>70%) form of VWD overall	DDAVP is usually effective unless VWF levels below around 10%–15%. VWF concentrate when DDAVP not effective
2A	Loss of high-molecular-weight VWF. Ratios of VWF:CB/VWF:Ag and VWF:RCo/VWF:Ag are typically both below 0.7	Most frequent form (∼30%) of type 2 VWD	DDAVP is only sometimes effective and should be trialed. VWF concentrate is most usually given
2B^b	Hyper-functional form of VWF yields response to lower concentrations of ristocetin in a RIPA assay. Loss of high-molecular-weight VWF sometimes observed, and ratios of VWF:CB/VWF:Ag and VWF:RCo/VWF:Ag can both be below 0.7	Rare form (∼10%–20%) of type 2 VWD	VWF concentrate is most usually given. DDAVP can be effective in some cases, but some experts are concerned about resulting potential thrombocytopenia
2M	Dysfunctional VWF. Laboratory test patterns depend on type of defect. Most common form is characterized by low VWF:RCo/VWF:Ag ratios (i.e. <0.7), but normal VWF:CB/VWF:Ag ratio	Under-recognized form of VWD. Probably nearly as common as type 2A	DDAVP is only sometimes effective and should be trialed. VWF concentrate is most usually given
2N^c	Defect in VWF preventing FVIII binding. Characterized by low relative plasma FVIII:C and identified by using a VWF–FVIII binding assay.	Rare form (∼10%–20%) of type 2 VWD	DDAVP is only sometimes effective and should be trialed. VWF concentrate is most usually given
3^d	VWF is absent. FVIII:C levels typically <10 U/dL	Rare except in developing countries	VWF concentrate (DDAVP is not effective)

^aAnti-fibrinolytics such as tranexamic acid are often also employed. Oral contraceptives can sometimes resolve menorrhagia in some women.

^bA rare platelet disorder called platelet type (PT-) VWD will give similar test results and should be distinguished from 2B VWD, as management differs. Differential diagnosis can be accomplished using RIPA-mixing studies or genetic analysis.

^c2N VWD cases are sometimes misdiagnosed as the more common hemophilia A; differential diagnosis requires performance of a test called the VWF–FVIII binding assay or genetic analysis.

^dType 3 VWD is sometimes also misdiagnosed as the more common hemophilia A; this can occur when VWF testing has been omitted from the investigation.

DDAVP = desmopressin; RIPA = ristocetin-induced platelet agglutination assay; VWF:CB = collagen binding assay for VWF; VWF:RCo = ristocetin co-factor assay for VWF; VWF = von Willebrand factor; VWD = von Willebrand disease.

Figure 3. Relative frequency of rare inherited bleeding disorders. Official data of the World Federation of Hemophilia (51).

Figure 4. Abnormalities of routine coagulations tests in patients with inherited coagulation factor (F) disorders. Some cases of VWD may also present with isolated prolongation of APTT (when low FVIII levels are also evident). Owren-based PT results may be normal in FV deficiency. Primary hemostasis defects such as thrombocytopenias and platelet function disorders should yield normal PT and APTT values.

Peyvandi F, Palla R, Menegatti M, Mannucci PM. Introduction. Rare bleeding disorders: general aspects of clinical features, diagnosis, and management. Semin Thromb Hemost. 2009;35:349–55.

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