Bleeding Disorders

Bleeding may result from abnormalities of
1. Platelets
2. Blood vessel walls
3. Coagulation.

Platelets disorders characteristically produce petechial and purpuric skin lesions and bleeding from mucosal surfaces. Defective coagulation results in ecchymoses, hematomas, and muscosal and, in some disorders, recurrent joint bleeding (hemarthroses).


Platelet Disorders
Thrombocytopenia.
Normal platelet count is 150.000-350.000/µL. Bleeding time, a measurement of platelet function, is abnormally increased if platelet count < 100.000/µL, injury or surgery may provoke excess bleeding. Spontaneous bleeding is unsual unless count < 20.000/µL, platelet count < 10.000/µL is often associated with serious hemorrhage. Bone marrow examination shows increased number of megakaryocytes in disorders associated with accelerated platelet destruction, decreased number in disorders of platelet production.


Causes
1. Production defects such as marrow injury (e.g. drugs, radiation), marrow failure (e.g., aplastic anemia), marrow invasion (e.g., carcinoma, leukemia, fibrosis).

2. Sequestration due to splenomegaly.

3. Accelerated destruction- causes include :

a. Drugs such as chemotherapeutic agents, thiazides, ethanol, estrogens, sulfonamides, quinidine, quinine, methyldopa.

b. Heparin-induced thrombocytopenic is seen in 5% of patients receiving >5 days of therapy and is due to in vivo platelet aggregation often from anti-platelet factor 4 antibodies. Arterial and occasionally venous thromboses may result.

c. Autoimmune destruction by an antibody mechanism, may be idiopathic or associated with systemic lupus erythematosus (SLE), lymphoma, HIV>

d. Idiopathic thrombocytopenic purpura (ITP) has two forms, an acute, self-limited disorder of childhood requiring no specific therapy, and a chronic disorder of adults (esp. woman 20-40 years). Chronic ITP may be due to autoantibodies to glycoprotein IIb-IIa or glycoprotein Ib-IX complexes.

e. Disseminated Intravascular Coagulation (DIC)-platelet consumption with coagulation factor depletion [prolonged prothrombin time (PT), partiaol thromboplastin time (PTT)] and stimulation of fibrinolysis [generation of fibrin split products (FSPs)}. Blood smear shows microangipathic hemolysis (schistocytes). Cause include infection (esp. meningococcal, pneumococcal, gram-negative bacteremias), extensive burns, trauma, or thrombosis, giant hemangioma, retained dead fetus, heat stroke, mismatched blood transfusion, metastatic carcinoma, acute promyelocytic leukemia.

f. Thormbotic thrombocytopenic purpura (TTP)-rare disorder characterized by microangipathic hemolytic anemia, fever, thrombocytopenia, renal dysfunction (and/or hematuria), and neurolofic dysfunction caused by failure to cleave von Willebrand factor (vWF) normally.

g. Hemorrhage with extensive transfusion.

Psudotheombocytopenia
Platelet clumping secondary to collection of blood in EDTA (0,3% of patients). Examination of blood smear establishes diagnosis.

Thrombocytosis
Platelet count >350.000/µL. Either primary (essential thrombocytosis) or secondary (reactive), later secondary to severe hemorrhage, iron deficiency, surgery, after splenectomy (transient), malignant neoplasms (esp. Hodgkin’s disease, polycythemia vera), chronic inflammatory disease (e.g. inflamatory bowel disease), recovery from acute infection, vitamin B12 deficiency, drugs (e.g., vincritistine, epinephrine). Rebound thrombocytosis may occur after marrow recovery from cytotoxic agents, alcohol. Primary thrombocytosis may be complicated by bleeding and /or thrombosis, secondary rarely causes hemostatic problems.

Disorders of Platelet Function
Suggested by the finding of prolonged bleeding time with normal platelet count. Defect is in platelet adhesion, aggregation, or granule release. Causes include :
1. Drugs-aspirin, other nonsteroidal anti-inflammatory drugs, dipyridamole, clopidogrel, heparin, penicillin, esp. carbenicillin,ticarcillin.
2. Uremia
3. Cirrhosis
4. Dysproteinemias
5. Myeloproliferative and myelodyplastic disorders
6. Von Willebrand disease
7. Cardiopulmonary bypass


Hemostatic Disorders Due to Blood Vessel Wall Defects
Causes include :
1. Aging
2. Drugs – e.g., glucocorticoid (chronic therapy), penicillins, sulfonamides.
3. Vitamin C deficiency
4. TTP
5. Hemolytic uremic syndrome
6. Henoch-Schonlein purpura
7. Paraproteinemias
8. Hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease)


Disorders of Blood Coagulation
Congenital Disorders
1. Hemophilia A-incidence 1:5000, sex-linked recessive deficiency of factor VIII (low plasma factor VIII (low plasma factor VIII coagulant activity, but normal amount of factor VIII-related antigen-vWF). Laboratory features, elevated PTT, normal PT).
2. Hemophilia B (Christmas disease)-incidence 1:30.000, sex linked recessive, due to factor IX deficiency. Clinical and laboratory features similar to hemophilia A.
3. Von Willebrand disease-most common inherited coagulation disorder (1:800-1000), usually autosomal dominant, primary defect is reduced synthesis or chemically abnormal factor VIII-related antigen produced by platelets and endothelium, resulting in abnormal platelet function.

Acquired Disorders
1. Vitamin K deficiency-impairs production of factors II (prothrombin), VII, IX, and X, vitamin K is a cofactor in carboxylation of glutamate residues on prothrombin complex proteins, major source of vitamin K is dietary (esp. green vegetables), with minor production by gut bacteria. Laboratory features : elevated PT and PTT.
2. Liver disease – results in deficiencies of all clotting factor except VIII. Laboratory features : elevated PT, normal or elevated PTT.
3. Other disorders-DIC, fibrinogen deficiency (liver disease,L-asparaginase therapy, rattlesnake bites), other factor deficiencies, circulating anticoagulants (lymphoma, SLE, idiopathic), massive transfusion coagulopathy).


17th Edition Harrison’s Manual of Medicine, 2009 Chap. 68. Bleeding and Thrombotic Disorders p. 332
For more detailed, see
Konkle BA : Bleeding and Thrombosis, Chap 59, p.363
Konkle BA : Disorders of platelets and Vessel Wall, chap 109, p. 718
Arruda V, High KA : Coagulation Disorders, chap 110, p.725
Weititz JI : Antiplatelet, Anticoagulant, and Fibrionolytic Drugs, chap 112, p. 735, in HPIM-17