Discuss the clinical, laboratory, and pathologic findings in a patient with Hemophilia A. (<250 words)

Hemophilia A is a coagulopathy that is caused by a deficiency of Factor VIIIAHF. The population incidence is 1/10,000, but this disease is inherited as an X-linked recessive trait, so that it is seen mostly in males, whereas females are usually only asymptomatic carriers. A third of cases may result from spontaneous mutations and present without a family history. Laboratory findings include an increased PTT with normal PT, platelet count, and bleeding time. Assay for clotting factors will show decreased VIIIAHF, with normal levels of other factors, including VIIIVWF.

The clinical presentation of Hemophilia A is one of increased bleeding into joints (hemarthrosis) and soft tissues. Bleeding into skin or gums, or petechial hemorrhages, are usually not present. This bleeding tendency is variable and correlates with the amount of Factor VIIIAHF present. If <1% is present as in most affected persons, there is spontaneous bleeding. If 1-5% of Factor VIIIAHF is present, bleeding may occur with minor trauma, and with 5-30% bleeding occurs with major trauma or surgery. Treatment may be given emergently with cryoprecipitate or fresh frozen plasma, but because of infection risk, the treatment of choice is heat-sterilized or recombinant Factor VIIIAHF products.

Discuss the major etiologies, laboratory findings, and pathologic consequences in a patient with disseminated intravascular coagulation (DIC). (<250 words)

Disseminated intravascular coagulation (DIC) is a disorder characterized by uncontrolled excess thrombin formation. The etiologies fall under two main categories. In the first, tissue factor is released in large quantities with such disorders as abruptio placenta, retained dead fetus, amniotic fluid embolus, malignancies (acute promyelocytic leukemia), or extensive trauma or burns. In the second, extensive endothelial damage results from gram-negative or severe gram-positive septicemia, other infections, or shock. Hemolytic transfusion reactions may also cause DIC.

The laboratory findings consistent with DIC include the very specific D-dimer assay as well as a positive protamine sulfate test or elevated fibrin degradation products (FDP's). Fragmented RBC's (schistocytes) appear in the peripheral blood. Consumption of clotting factors leads to a prolonged prothrombin time and partial thromboplastin time. Platelets are decreased and the bleeding time is prolonged.

The pathologic consequences of DIC include both bleeding and thrombosis. The bleeding paradoxically occurs because of the consumption of coagulation factors, activation of the fibrinolytic pathways, and production of FDP's which all inhibit coagulation. Thrombosis, which can be extensive with microthrombi in small vessels, can lead to areas of ischemia and infarction in multiple organs (brain, kidney, heart, etc.). However, bleeding is more common than thrombosis.

Treatment of DIC involves use of heparin to halt the uncontrolled thrombin formation along with fresh frozen plasma (FFP) to make up for the coagulation factor deficiencies. However, the prime method of treatment must be to determine the underlying cause and treat that.

Discuss the possible causes and the subsequent pathologic findings that could occur with femoral vein thrombosis. (<250 words)

Femoral vein thrombosis occurs most frequently when there is venous stasis from immobilization, typical for hospitalized patients. Direct injury to the vessel or surrounding inflammation may also promote venous thrombosis. This may occur with an intravenous catheter. Hypercoagulability can predispose to thrombosis and can result from congenital deficiencies of anticoagulant factors such as Protein C or Protein S, malignancies, increased age, and use of oral contraceptives.

Once a thrombus has formed, there are several possibilities. Acutely, the venous stasis may lead to increase swelling of the extremity, particularly if the thrombus continues to propagate. The thrombus may undergo lysis and/or organization within the vessel over the next several weeks, returning circulation to normal. The worst complication is embolization. A femoral vein thrombus could travel up the inferior vena cava, through the right heart, and into the pulmonary arterial circulation. What happens next depends upon the size of the thromboembolus. A large embolus could occlude the main pulmonary arteries and cause sudden death. A medium-sized embolus could occlude a segmental arterial branch and lead to a hemorrhagic infarction of lung. Multiple small thromboemboli could occlude peripheral pulmonary arteries and lead to pulmonary hypertension.

Explain how you would work up a patient who is found to have thrombocytopenia. (<250 words)

Thrombocytopenia can occur acutely with marked hemorrhage and volume replacement, but it more often represents an ongoing problem related to either decreased platelet production by megakaryocytes in marrow or to increased peripheral consumption or destruction. A bone marrow biopsy is performed to determine if there has been an idiopathic or drug related marrow aplasia with decreased megakaryocytes. A drug history should be obtained. The biopsy may also reveal the presence of a myelophthisic process with marrow replacement by metastatic carcinoma, leukemia, granulomatous infection, or myelofibrosis. Increased peripheral platelet consumption can occur with disseminated intravascular coagulation (DIC), and a d-dimer test and the presence of RBC fragmentation on a peripheral blood smear are indicators of this process, along with a prolonged protime and partial thromboplastin time. Thrombotic thrombocytopenic purpura (TTP) can also lead to platelet consumption, and can be diagnosed from finding transient neurologic deficits, renal failure, and fever. Platelets can also be sequestered in a large spleen, detected by physical examination or radiographic scan, as can be seen with the congestive splenomegaly of cirrhosis, with certain hemoglobinopathies such as hereditary spherocytosis, and with infections such as malaria. The peripheral destruction of platelets can occur with autoantibodies directed against platelets, as with idiopathic thrombocytopenic purpura (ITP). A bone marrow biopsy with ITP and other causes for peripheral platelet consumption will demonstrate megakaryocytic hyperplasia.