I) Hypocoagulable disorders
Hemophilias: Hemophilia is a bleeding disorder caused by deficiency of either factor VIII or factor IX.
Hemophilia A and B are inherited in an X-linked recessive pattern, so they’re more common in males. Hemophilia A is more common than hemophilia B. About 10% of carrier females have less than half the normal level of one of these coagulation factors and are at risk for abnormal bleeding, especially after injury, surgery, or tooth extraction.
Mutations in the F8 gene cause hemophilia A, and mutations in the F9 gene cause hemophilia B. These genes code for factor VIII and factor IX, respectively.
Acquired hemophilia occurs in adulthood and results from autoantibodies to factor VIII. It may occur in pregnancy, SLE, drug allergies, autoimmune diseases, or cancers.
Another rare form is hemophilia B Leyden, which is associated with severe bleeding in childhood but few bleeding problems after puberty.
Laboratory findings
Treatment
Cryoprecipitate and fresh frozen plasma are NO longer recommended for treatment of individuals with hemophilia A or B.
Emicizumab (Hemlibra) is a monoclonal antibody that substitutes for part of the cofactor function of activated factor VIII (FVIIIa) by bridging activated factor IX (FIXa) and factor X (FX). It is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia A.
Patients with autoantibodies to factor VIII or IX are treated with recombinant factor VIIa or activated prothrombin complex concentrates (the latter is contraindicated if the patient is on emicizumab).
Aspirin and aspirin-containing products should be avoided in individuals with hemophilia unless there is a cardiac indication.
Von Willebrand disease or VWD: Von Willebrand disease is the most common genetic bleeding disorder. It is caused by mutations in the VWF gene on chromosome 12, which codes for von Willebrand factor.
| Type | Features |
| Type 1 | Most common; milder symptoms; low levels of vWF in blood; FVIII may be low; present with mild mucocutaneous bleeding, nosebleeds, bruising, heavy menstrual bleeding; most cases are AD, some AR. |
| Type 2 | Mild to severe symptoms; vWF levels are near normal or normal, functional defect; most cases AD, some AR; type 2A vWF cannot bind platelets; type 2B has thrombocytopenia; type 2M decreased activity of vWF and cannot interact with platelets; type 2N failure of vWF to transport FVIII to the site of injury. |
| Type 3 | Severe symptoms, AR; almost complete absence of vWF in blood; severe mucocutaneous bleeding, bleeding into joints and muscles, hematomas, PPH. |
Acquired von Willebrand disease is rare and can be seen in multiple myeloma, cardiac defects, essential thrombocythemia, some cancers, autoimmune diseases, diabetes mellitus, and drugs such as valproic acid. It occurs due to the development of autoantibodies to vWF.
Platelet type VWD (pseudo-VWD) is a rare platelet disorder caused by abnormally high affinity of platelets to vWF due to mutations in GPIb. It is an AD condition and presents clinically similar to VWD. Bleeding time is prolonged, and thrombocytopenia is seen.
Diagnosis is based on clinical features and laboratory testing:
Treatment
Mild cases may need treatment before planned surgeries or dental procedures.
Drugs affecting blood clotting such as aspirin, warfarin, heparin, and NSAIDs should be avoided.
Fibrinogen deficiency: This includes afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia.
Decreased fibrinogen (factor I) levels (hypofibrinogenemia) can be seen in DIC, liver failure, massive transfusion, cardiopulmonary bypass, severe hypothermia and acidosis after major trauma, and in some congenital cases (AD or AR).
In some cases, congenital afibrinogenemia is present and is inherited as AR. These disorders are caused by mutations in fibrinogen genes FGA, FGB, or FGG.
Clinical features may include umbilical bleeding at birth, ICH, epistaxis, GI bleeding, splenic rupture, myalgia, hematemesis, tarry stools, hematochezia, ecchymoses, gingival bleeding, haemarthroses, menorrhagia, recurrent abortions, and PPH.
There is increased risk of PE, AMI, and strokes due to abnormally increased thrombosis. ESR may be low.
Laboratory findings
Treatment
In dysfibrinogenemia, fibrinogen is functionally defective. Patients may present with delayed wound healing, rupture of surgical stitches, skin necrosis, miscarriages, stillbirths, and paradoxically increased thrombosis.
Factor XIII deficiency: This presents like other bleeding disorders but with normal PT and APTT/PTT. The clot solubility test will be positive (the clot will lyse) in severe cases. Factor XIII assay will show low levels.
Treatment is with factor XIII concentrates (preferable), although FFP (fresh frozen plasma) or cryoprecipitate can also be used.
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