VON WILLEBRAND DISEASE
* von Willebrand disease (vWD) is a disorder of primary hemostasis (difficulty forming the initial platelet plug) due to defective interaction between platelets and vessel walls.
* Since von Willebrand factor (vWF) is also a carrier of factor VIII, patients can have secondary hemostasis problems as well (failure to form the fibrin clot).
* Severe disease due to very low functioning vWF is rare. A single allele produces a state with varied penetrance, while two alleles result in significant disease.
* vWD is an autosomal dominant dis order with an estimated incidence of 1:100 to 1:400 (the most common inherited bleeding disorder).
* Prevalence is equal among males and females, but vWD is more problematic in females because of menorrhagia.
* The three types of vWD are
- Type I ‐ partial quantitative deficiency (75%‐80% of cases)
- Type II ‐ qualitative deficienc
- Type III ‐ total deficiency
* People with vWD usually have mild to moderate bleeding (nosebleeds, menorrhagia, gingival bleeding, bruising) and bleeding related to trauma or surgery.
* Bleeding after minor trauma is often increased.
* Severe hemorrhage during surgery is less common; however, delayed bleeding after surgery is a hallmark of the disease.
* Increased bleeding after dental extraction or oral surgeries is also common. Aspirin use causes markedly increased bleeding.
* Physical examination is usually normal except for bruising.
* Bleeding time will be prolonged.
* Platelet count will be in the normal range.
* Prothrombin time (PT) will be normal, but activated partial thromboplastin time (aPTT) can be normal or prolonged, depending on severity of the disease.
* Functional assay: vWF‐RIPA (ristocetin‐induced platelet aggregation) and vWF multimer studies help distinguish subtypes of vWF.
* Factor VIII activity can be normal or abnormal.
* Desmopressin acetate (DDAVP) can be used for mild bleeding, minor procedures, or trauma. It is also available as a nasal spray for prophylaxis before minor surgery.
* Oral contraceptives often help in managing menorrhagia in females.
* Cryoprecipitate may be required for severe bleeding or postoperatively.
* Factor VIII concentrate rich in vWF may also be used in severe bleeding.
IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP)
* ITP is also known as immune thrombocytopenic purpura.
* Increased bleeding is due to a low platelet count.
* Childhood ITP manifests as acute onset bruising or petechiae. It can follow viral infection and is more common in boys.
* Adult ITP is more common in women. It presents between the ages of 20 and 50 years and can develop after viral infection, exposure to drugs, or pregnancy (less common).
* ITP can be acute and nonrecurrent in children but is usually recurrent in adults.
* Isolated thrombocytopenia and purpura are typical findings in an otherwise well‐appearing patient.
* ITP is a disease of exclusion; elimi nate other possible causes of low platelet counts, including leukemia and aplastic anemia.
»QUESTION & ANSWER
1. The patient is a 25‐year‐old female who presents because her dentist noted prolonged bleeding after extraction of two wisdom teeth. The patient has a history of menorrhagia and notes that her mother had the same problem. Physical examination findings are unremarkable except for some bruising in her lower extremities, which the patient explains are due to “my usual clumsiness.” She denies any easy bleeding in the past. CBC is normal. Which of the following results would you expect to see?
a. Increased prothrombin time (PT)
b. Increased activated partial thromboplastin time (aPTT)
c. Increased bleeding time
d. Decreased factor IX assay
Explanation: This patient has the classic history for von Willebrand disease, which would result in an increased bleeding time with normal PT and aPTT.
* Bleeding can range from mild (bleed ing gums, menorrhagia, petechiae) to severe (GI or CNS bleeding).
* In adult ITP, platelet counts are usually <30×109/L (patients may be asymptomatic if counts reach 50×109/L).
* In childhood ITP, platelet counts are usually <20×109/L.
* Mucosal bleeding, such as nosebleeds or menorrhagia, is common in adults.
* Bruising or petechiae are present in both childhood and adult forms.
* Examination should include the skin for petechiae and ecchymosis, the conjunctivae, retinas, and CNS.
* No specific diagnostic test exists.
* Platelet count will be low.
* Bleeding time is prolonged.
* Peripheral smear shows megathrom bocytes due to early release from the bone marrow.
* Bone marrow studies are done to rule out other disorders but may show increased megakaryocytes and can rule out pseudothrombocytopenia.
* Antiplatelet antibodies may be present, but these are not specific.
* Some cases of acute ITP may resolve spontaneously.
* No treatment is necessary if the platelet count is >30×109/L.
* Prednisone can be given for mild bleeding, daily if necessary in recurrent cases.
* Oral dexamethasone may be required in more severe cases.
* IgG (or anti‐D globulin in Rh‐positive patients) is sometimes used.
* Danazol may be helpful in female patients.
* Splenectomy may provide definitive treatment.
* If not resolved after splenectomy, immune modulator drugs may be used
* Thrombopoietin receptor agonists (eltrombopag or romiplostim)
THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP)
* TTP, also known as microangio pathic thrombocytopenia purpura, is a rare inherited or acquired disorder.
* Untreated, the mortality of TTP is very high, so treatment is urgent.
* TTP is characterized by a classic pentad: fever, thrombocytopenia, microangiopathic hemolytic anemia, renal insufficiency, and neurologic signs, although only about 25% of patients have all five findings.
* TTP may manifest with hemolytic anemia and thrombocytopenia but more commonly manifests with a thrombotic event.
* TTP may be associated with vWF deficiency.
* Exposure to toxic or infectious agents produces endothelial cell damage and vascular injury that inhibits fibrinolysis and results in platelet aggregation and thrombosis.
* Signs and symptoms resulting from thrombus formation, anemia, or mucocutaneous bleeding
- Pallor, orthostasis, and other signs of anemia
- Bleeding gums, nosebleeds, men orrhagia, bruising, purpura
- Abdominal pain, nausea, vomiting secondary to enteric ischemia
- Renal function may be normal or may demonstrate acute renal insufficiency.
- CNS symptoms: headache, somnolence, delirium, seizures, paresthesias, and coma (due to microthrombi)
* TTP can occur in the setting of HIV infection, pregnancy, or cancer and with the use of certain drugs (eg, cyclosporine, quinine, ticlopidine, clopidogrel, mitomycin C, and bleomycin).
* In addition to thrombocytopenia, laboratory results are consistent with hemolytic anemia: increased lactate dehydrogenase (LDH) and indirect bilirubin; decreased haptoglobin; negative direct antiglobulin test; schistocytes and reticulocytosis on peripheral smear.
* PT and aPTT, fibrinogen, and D‐dimer
* values will be normal, but bleeding time is prolonged.
* TTP can be differentiated from hemolytic‐uremic syndrome (HUS) by presence of fever (unusual in HUS), absence of diarrhea (common in HUS), and decreased activity of ADAMTS‐13 (the vWFcleaving protease, which is usually normal in HUS).
* Plasma exchange is urgently needed—usually every 24 hours until platelet count and LDH are normal on 2 consecutive days. Then gradually decrease frequency, and monitor platelet count and LDH.
* If plasmapheresis is unavailable, fresh frozen plasma may be given as a temporizing measure.
* Immunosuppressive therapy is used in some cases.
* Platelet transfusion is contraindi cated because it may increase the tendency to form thrombi. (In severe cases, however, it may be given once plasmapheresis has started.)
* Consider RBC transfusion and hemodialysis in severe cases.