Disorders of coagulation

I) Hypocoagulable disorders

Hemophilias: It is a bleeding disorder that occurs due to deficiency of either Factor VIII or IX. Accordingly, it is called Hemophilia A or classic hemophilia, which is Factor VIII deficiency; while factor IX deficiency is called Hemophilia B or Christmas disease. Hemophilia A and hemophilia B are inherited in an X-linked recessive pattern, so they are more common in males, with Hemophilia A being more common. About 10% of carrier females have less than half the normal amount of one of these coagulation factors and are at risk for abnormal bleeding, particularly after an injury, surgery, or tooth extraction.

Mutations in the F8 gene are responsible for hemophilia A, while mutations in the F9 gene cause hemophilia B, which code for Factor VIII and Factor IX respectively.

Grades of Hemophilia A

• Mild: 6-49% of FVIII in the blood; bleeding after trauma or surgery, prolonged bleeding after tooth extraction, menorrhagia, PPH
• Moderate: 1-5% of FVIII in the blood; bleeding after injuries; spontaneous bleeding episodes
• Severe: <1% of FVIII in the blood; bleeding after injury, frequent spontaneous bleeding into joints and muscles

Acquired hemophilia is seen in adulthood and results from autoantibodies to Factor VIII which may happen 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 has few bleeding problems after puberty.

Laboratory findings include prolonged clotting time, APTT/PTT is prolonged, normal bleeding time, normal PT and assays will show reduced levels of involved factor. Hemophilia A is treated with preferably recombinant Factor VIII precipitate, desmopressin and aminocaproic acid. Plasma derived Factor VIII can be used in emergency situations when recombinant form is not available. Cryoprecipitate and fresh frozen plasma are NO longer recommended for treatment of individuals with hemophilia A or B. Treatment of Hemophilia B is with recombinant Factor IX and aminocaproic acid.

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 a novel drug 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, that codes for von Willebrand factor.

Types of von Willebrand disease

Acquired von Willebrand disease is a rare disorder that is 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 auto-antibodies to vWF.

Platelet type VWD or pseudo-VWD is a rare disorder of platelets, caused by abnormally high affinity of platelets to vWF, caused by mutations to GPIb. It is an AD condition and presents similar to VWD clinically. Bleeding time is prolonged and thrombocytopenia is seen.

Diagnosis is by clinical features and by measuring the level of vWF in blood by ELISA. Levels of vWF are affected by the blood group and are typically lower in type O blood group individuals. APTT may be normal or increased, PT is normal and platelet count may be normal or low . CBC may show microcytic hypochromic anemia. FVIII levels will be low. Ristocetin cofactor assay and RIPA can be used as qualitative functions. vWF multimer test can be done to determine type of VWD. Molecular genetic testing can be done to identify known mutations.

Mild cases need treatment before planned surgeries or dental procedures. Desmopressin stimulates release of vWF from stores in endothelial cells. It is contraindicated in type 2B as it can further decrease the platelet count. Desmopressin is ineffective in severe cases. Such cases are treated with concentrates of vWF and FVIII. Fibrin glue can be applied locally to minor cuts and dental procedures. Hormonal contraceptive pills increase levels of vWF in the blood. Tranexamic acid and aminocaproic acid can be used as adjunct therapy. Drugs affecting blood clotting such as aspirin, warfarin, heparin and NSAIDs should be avoided.

Fibrinogen deficiency: It is seen in afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia and hypodysfibrinogenemia. Decreased fibrinogen (factor I) levels or hypofibrinogenemia is 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 a few cases, congenital afibrinogenemia is present, which is inherited as AR. They are caused by mutations in fibrinogen genes FGA, FGB or FGG. Patients present with 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. PT, APTT and TT (thrombin time) are prolonged. Depending on the condition, fibrinogen levels in blood will be either low or absent. Treatment is with fresh frozen plasma, cryoprecipitate and fibrinogen concentrates (preferred). Tranexamic acid or epsilon-aminocaproic acid can be used as supplemental therapy.

In dysfibrinogenemia, fibrinogen is functionally defective. Patients with dysfibrinogenemia present with delayed wound healing, rupture of surgical stitches, skin necrosis, miscarriages, stillbirths and paradoxically increased thrombosis.

Factor XIII deficiency: Presents like any other bleeding disorder but has normal PT and APTT/PTT. Clot solubility test will be positive (clot will lyse) in severe cases. Assay for factor XIII will show low levels. It is treated with Factor XIII concentrates (preferable), although FFP (fresh frozen plasma) or cryoprecipitate can also be used.