Disorders of Primary Hemostasis

1. 33 Disorders of Primary Hemostasis

2. Learning Objectives—Level I At the end of this unit of study, the student should be able to: • Define and differentiate among thrombocytopenia, thrombocytosis, and thrombocythemia and state an expected range of platelet count in each. • Define and differentiate among petechiae, purpura, ecchymosis, hematoma, and easy bruisability. continued on next slide

3. Learning Objectives—Level I At the end of this unit of study, the student should be able to: • Identify laboratory tests that can be ordered to screen for abnormalities of the hemostatic system. • Explain the expected clinical consequences when a patient has an abnormality of platelets or blood vessels. continued on next slide

4. Learning Objectives—Level I At the end of this unit of study, the student should be able to: • Correlate quantitative variations in the platelet count with disease manifestations. • Recognize hematologic disorders that are characterized by the presence of thrombocytopenia or thrombocytosis. continued on next slide

5. Learning Objectives—Level I At the end of this unit of study, the student should be able to: • Describe the etiology, pathophysiology, and laboratory findings of the thrombocytopenias. • Differentiate primary (malignant) from secondary (reactive) thrombocytosis. continued on next slide

6. Learning Objectives—Level I At the end of this unit of study, the student should be able to: • Explain the effect of aspirin and its duration on platelet function. • Identify the cause and describe the clinical and laboratory features of hereditary disorders of platelet function.

7. Learning Objectives—Level II At the end of this unit of study, the student should be able to: • Categorize each specific disorder of hemostasis by body system affected (e.g., vasculature, platelets). • Predict the type of bleeding symptoms in patients with disorders of primary hemostasis. continued on next slide

8. Learning Objectives—Level II At the end of this unit of study, the student should be able to: • Describe the expected symptomatology, etiology, pathophysiology, and laboratory test results in patients with disorders of the vasculature. • Organize thrombocytopenic and thrombocytosis conditions by etiology and pathophysiology and explain laboratory findings in each condition. continued on next slide

9. Learning Objectives—Level II At the end of this unit of study, the student should be able to: • Differentiate acute from chronic immune thrombocytopenia by significant clinical and laboratory data. • Explain the pathophysiology of thrombocytopenia and thrombocytosis in hematologic disorders. continued on next slide

10. Learning Objectives—Level II At the end of this unit of study, the student should be able to: • Organize the hereditary and acquired qualitative platelet defects by etiology and pathophysiology, and predict the clinical and laboratory features. continued on next slide

11. Learning Objectives—Level II At the end of this unit of study, the student should be able to: • Explain the biochemical mechanism of the effect of aspirin on platelet function and recommend a time frame for patients to refrain from taking aspirin and related anti-inflammatory drugs prior to platelet function testing. • Summarize the effect of aspirin, alcohol, and antibiotics on platelet function.

12. Clinical Manifestations of a Bleeding Disorder • Defect in primary hemostasis • Skin or mucous membrane bleeding (e.g., nose, gums) • Defect in secondary hemostasis • Deep tissue/joint bleeding

13. Bleeding Manifestations in Intact Skin • Petechiae (< 3 mm) • Blood leakage through capillaries • Purpura (3 mm–1 cm) • Intermediate lesions • Ecchymoses (> 1 cm) • Blood leakage into subcutaneous tissue from larger vessel

14. Bleeding Manifestations in Intact Skin • Hematoma—blue or purple raised area • Blood leakage from vessel and collecting beneath intact skin

15. Figure 33-1 Schematic drawing of bleeding manifestations in intact skin. (a) Petechiae. (b) Ecchymosis. (c) Hematoma.

16. Easy Bruising • Common manifestation in disorders of primary hemostasis • Presence on trunk without recognized trauma more significant than on limbs in absence of trauma • Patients may also report excessive and prolonged bleeding from cuts.

17. Patient History • Age of onset of hemorrhagic symptoms • Type of symptoms • Family history • Presence of other diseases • Complete drug history • Exposure to toxins

18. Lab Evaluation of Abnormal Bleeding • Laboratory tests of coagulation and hemostasis • Should not be a substitute for clinical assessment • Screening tests • No single test can fully evaluate defective hemostasis • Not helpful in predicting bleeding risk

19. Typical Screening Test Profile • Prothrombin time (PT) • Activated partial thromboplastin time (APTT) • Quantitative platelet count

20. Disorders of Primary Hemostasis • Screening tests are often normal. • May need confirmatory platelet function tests • Closure time (platelet function analyzer) • Platelet aggregation tests • Flow cytometry for platelet antigens

21. Disorders of the Vascular System

22. Primary Vascular Disorders • Most are not associated with platelet or plasma defects. • Most common symptom • Abnormal bleeding into or under the skin • Laboratory tests used to exclude • Coagulation or platelet disorders

23. Primary Vascular Disorders • Majority of patients • Hemostatic testing is entirely normal, despite history or physical examination that suggests substantial bleeding. • Confirmation • Usually requires histologic evaluation of vessel or connective tissue

24. Vascular Disorders—Inherited • Hereditary hemorrhagic telangiectasia (HHT) • Arteriovenous malformations— Hemangiomas • Ehlers-Danlos Syndrome • Joint hypermobility • Osteogenesis Imperfecta • Defective bone matrix

25. Vascular Disorders—Inherited • Pseudoxanthoma elasticum • Calcification of elastic fibers • Marfan syndrome • Overgrowth of long bones

26. Table 33-1 Characteristics of Inherited Disorders of the Connective Tissue

27. Vascular Disorders—Inherited • Hemangiomas • Composed of tangled masses of dilated thin-walled venules (arteriovenous malformations) • Usual causes • Upregulation of growth-promoting factors and/or inhibition of apoptosis continued on next slide

28. Vascular Disorders—Inherited • Hemangiomas • Strawberry hemangiomas • Superficial, located in the skin, occur early in life, often regress by adolescence

29. Vascular Disorders—Acquired • Purpura from decreased supportive connective tissue • Senile purpura—degeneration of skin matrix • Cushing syndrome—excess glucocorticoids • Scurvy—Vitamin C deficiency

30. Vascular Disorders—Acquired • Purpura associated with dysproteinemias • Paraproteins—affect platelets, coagulation factors, bind Ca++, and so on • Amyloidosis—vessel fragility with bleeding and thrombosis

31. Vascular Disorders—Acquired • Purpura from vasculitis • Vasculitis • Inflammation of small blood vessels • Immune complexes form • Attach to vessel and activate complement • May cause platelet aggregation, FXII and kallikrein activation with release of kinins from HK continued on next slide

32. Vascular Disorders—Acquired • Purpura from vasculitis • Vasculitis • Immune complexes form • Vessel damage with edema and inflammation • Results in purpura—palpable purpura (nodules form at site) • Causes • Henoch-Schönlein purpura, infections, drugs, idiopathic

33. Vascular Disorders—Acquired • Miscellaneous causes of purpura • Mechanical purpura • Increased pressure in vessel lumen • Artificially induced purpura • Self-inflicted continued on next slide

34. Vascular Disorders—Acquired • Miscellaneous causes of purpura • Easy Bruising Syndrome • Occurs mostly in young women as result of vascular fragility • Purpura Fulminans • Abnormalities of clotting factors or their inhibitors

35. Table 33-2 Classification of Acquired Disorders of the Vascular System

36. Table 33-3 Types of Bleeding in Disorders of Primary Hemostasis

37. Table 33-4 Significant Laboratory Tests in Defects of Primary Hemostasis

38. Platelet Disorders

39. Platelet Disorders • Quantitative • Thrombocytopenia • Thrombocytosis • Qualitative • Morphologic abnormalities • Macrothrombocytes (giant platelets) • Microthrombocytes • Hypogranular or agranular platelets

40. Figure 33-2 (a) Large granular platelet. (b) Increased numbers of platelets, some of which have normal morphology, some of which are hypogranular, and several giant platelets (peripheral blood, Wright-Giemsa stain, 1000× magnification).

41. QuantitativePlatelet Disorders

42. Table 33-5 Classification of Quantitative Platelet Abnormalities

43. Thrombocytopenia • Platelet count • < 150 × 109/L • Usually no↑risk of bleeding unless < 50 × 109/L • Risk of severe and spontaneous bleeding when platelet count is < 10 × 109/L

44. Thrombocytopenia • Bleeding from mucous membranes • GI, GU tract, and so on • Bleeding into CNS • PT, APTT, and fibrinolytic system tests are unaffected by thrombocytopenia

45. Table 33-6 Classification of Thrombocytopenia Caused by Increased Destruction

46. Increased Destruction • Immune-mediated • Antibodies • Bind to epitopes on GPIIb/IIIa or • Attach to platelet Fc receptors • Platelets sensitized with antibody are removed by mononuclear phagocyte system • Primarily spleen, secondarily liver continued on next slide

47. Increased Destruction • Immune-mediated • No routine tests to evaluate immunoglobulin on platelets • BM—↑ MKs; ↑ ploidy; ↑platelet production • Stimulation by TPO

48. Figure 33-4 Mechanisms of thrombocytopenia caused by immune destruction of platelets. In immune thrombocytopenia, Fc receptors of the splenic macrophages (M) recognize antibody-sensitized platelets and eliminate them from the circulation. The bone marrow is stimulated by thrombopoietin (TPO) and produces increased numbers of megakaryocytes. Thrombocytopenia develops if immune destruction exceeds the compensatory capacity of the marrow. The antibody can also injure megakaryocytes.

49. Immune Thrombocytopenia (ITP) • Formerly called immune thrombocytopenia purpura • Most common form of thrombocytopenia • Primary/idiopathic or secondary

50. Immune Thrombocytopenia (ITP) • Autoreactive antibodies from B lymphocytes bind to platelet • Shorten life span • Abnormal regulatory T-cells and loss of T-cell tolerance • Accumulation of cytotoxic T-cells