Quantitative and qualitative platelet disorders

1. Quantitative and qualitative platelet disorders Prof. Dr. Sami Kartı

2. Quantitative Disorders of Platelets

3. Thrombocytosis • Thrombocytosis is defined as a platelet count exceeding the upper limit of the reference range. A value of >400,000 platelets/μL (>400 X 10E9/L) can be used as a guideline; • Thrombocytosis is usually secondary to some other condition (reactive thrombocytosis) and is not associated with an increased risk of thrombosis or other complications. • Primary thrombocythemia, on the other hand, may be associated with thrombosis or bleeding. • Reactive thrombocytosis is far more common than primary thrombocythemia.

4. Causes of Thrombocytosis • Infection • Inflammation • Malignancy (myeloproliferative disorders, non-hematologic malignancies) • Post-splenectomy (thrombocytosis is common during the first weeks or months following splenectomy) • Iron deficiency • Miscellaneous (acute hemorrhage or trauma, surgery, acute hemolysis, and transiently after an episode of thrombocytopenia-rebound thrombocytosis)

8. Treatment of Thrombocytosis • Reactive thrombocytosis is not associated with increased risk of either thrombosis or hemorrhage, and treatment of the thrombocytosis per se is unnecessary • The underlying cause of thrombocytosis should be identified and treated appropriately

9. Thrombocytopenia • Thrombocytopenia is defined as a platelet count below the reference range for a particular laboratory; <150,000/μL can be used as a rough guide • The consequence of thrombocytopenia is risk of hemorrhage. In general, the risk of hemorrhage correlates with the platelet count • A platelet count >100,000/μL is associated with no risk of hemorrhage, even with surgery • A platelet count <5,000/μL is associated with a significant risk of spontaneous severe hemorrhage • The relationships between platelet count and risk of hemorrhage may not be valid if the patient has a primary platelet disorder, is on medication that interferes with platelet function, or has other risk factors for bleeding

11. Artifactual thrombocytopenia (pseudothrombocytopenia) Causes of pseudothrombocytopenia • platelet clumping (the most common cause of pseudothrombocytopenia) • platelet satellitism around neutrophils • hereditary giant platelet syndromes • a clotted specimen, or an old specimen

14. Manifestations of Thrombocytopenia Mucocutaneous bleeding • Petechiae (pin-point cutaneous hemorrhages) • Cutaneous purpura • Gingival bleeding • Epistaxis (nosebleeds) • Menorrhagia • Gastrointestinal bleeding hematuria • Intracranial hemorrhage is the most serious complication but is uncommon. ➪ Deep visceral hematomas, hemarthroses, or muscle hematomas are uncommon with thrombocytopenia and suggest a defect in the coagulation cascade.

17. Evaluation of Thrombocytopenia (I) • Review a blood smear to exclude platelet clumping or other cause of pseudothrombocytopenia. • Always think about the possibility of HIV infection in any young patient with thrombocytopenia or any person with risk factors for HIV. Thrombocytopenia may be the first manifestation of HIV and may occur early in the infection. • Consider the clinical setting. • A patient in the intensive care unit could have many possible causes of thrombocytopenia, such as medications (including heparin), sepsis, and disseminated intravascular coagulation. • Thrombocytopenia in a pregnant woman raises a completely different differential, including preeclampsia, HELLP syndrome, or gestational thrombocytopenia.

18. Evaluation of Thrombocytopenia (II) • History • Ask how long the patient has had bleeding symptoms • Determine if the patient has had a previous platelet count and whether the count was normal or decreased • Ask if there is any family history of thrombocytopenia • Ask about recent symptoms of infection, skin rashes, arthritis, and other symptoms of SLE or other autoimmune diseases • Medication history • Ask about over-the-counter medications, dietary supplements, and dietary and herbal supplements, particularly quinine • Physical examination • Look for petechiae, purpura, and other signs of bleeding. Carefully palpate for lymphadenopathy or a palpable spleen

19. Evaluation of Thrombocytopenia (III) Laboratory • CBC: Abnormalities in the white cell count or anemia • Blood smear: Look for schistocytes, blasts, or other immature or abnormal cells. • Serum chemistries: Liver enzymes should be checked to exclude viral hepatitis. • Serologies for autoimmune disease • HIV test: Serologies for HIV should be checked in any patient at risk (some people suggest that new-onset thrombocytopenia in any-one is a reason to check HIV serologies). • Bone marrow: A bone marrow examination is probably not necessary in the absence of other hematologic abnormalities, but one should be performed if other hematologic abnormalities are present.

20. Treatment of Thrombocytopenia • Any precipitating cause should be treated appropriately • All possible medications should be discontinued, including heparin, quinine, and other drugs known to be associated with thrombocytopenia • Drugs that might interfere with platelet function (ie, aspirin) should be avoided • If the thrombocytopenia is not severe and there is no evidence of bleeding, the patient may be observed • Corticosteroids or intravenous immunoglobulin may be given for suspected immune thrombocytopenia • If the patient is severely thrombocytopenic and there is evidence of bleeding, platelet transfusions can be given • The decision to treat a patient for thrombocytopenia should depend on the clinical condition of the patient, not the platelet count

21. Idiopathic Autoimmune Thrombocytopenic Purpura Acute Idiopathic Autoimmune Thrombocytopenic Purpura • Acute ITP usually occurs in children between 2 and 6 years of age • Sudden onset of petechiae, often beginning a few weeks after a viral infection (may also follow vaccinations) • The thrombocytopenia can be severe, but bleeding manifestations are usually mild • Spontaneous recovery occurs in up to 90% of cases. The duration of illness varies from a few days to 6 months, with an average of 4 to 6 weeks • No treatment is required in most cases, and recurrence is unusual. ➪A clue to acute ITP in childhood: the child looks much better than the platelet count.

22. Chronic Idiopathic Autoimmune Thrombocytopenic Purpura • Chronic ITP is most common in adults • The onset is usually insidious • There is no history of preceding infection • It occurs more often in women than in men (~3:1), and most cases occur in young adults (~70% below age 40 years) • The course tends to be fluctuating, with episodes of thrombocytopenia lasting a few weeks or months • Multiple recurrences are common, and spontaneous long-term remissions are rare

23. Diagnosis of Chronic ITP (I) • Idiopathic autoimmune thrombocytopenic purpura is largely a diagnosis of exclusion • The diagnosis of ITP is based predominantly on history, physical examination, CBC, and blood smear. • The history should exclude other possible causes of thrombocytopenia (drugs, HIV or other infections, autoimmune disorders) • The physical examination in ITP should be unremarkable • The presence of lymphadenopathy or more than mild splenomegaly suggests an underlying lymphoproliferative disorder • The blood smear should confirm thrombocytopenia

24. Diagnosis of Chronic ITP (II) • There should be no evidence of other hematologic diseases such as acute leukemia, CLL, myelodysplasia, or thrombotic thrombocytopenic purpura • If there is no other cause for thrombocytopenia detected by history, physical, CBC, and blood smear, then the patient probably has ITP and should be treated as such • In most cases, no further diagnostic tests are necessary • A bone marrow examination should be considered in older patients (over ~60 years) or before splenectomy is performed • It should also be performed if there are any abnormalities on CBC or blood smear other than thrombocytopenia • A bone marrow examination is usually not needed in young patients with no evidence of other hematologic diseases

25. Treatment of Chronic ITP (I) • The goal of therapy in patients with chronic ITP is to prevent serious bleeding, not to normalize the platelet count. Patients with chronic ITP may tolerate astonishingly low platelet counts with no or minimal bleeding, and the side effects from therapy may be more problemmatic than the low platelet count itself. • Corticosteroids: Corticosteroids are the standard initial therapy for ITP. • Prednisone or equivalent is started at ~1 to 2 mg/kg per day, maintained at that dose for ~3 to 4 weeks, and then slowly tapered over 1 to 4 months. • The platelet count usually begins to rise within 1 week and reaches a maximum by 2 to 4 weeks • Approximately 65 to 85% of patients respond to corticosteroids

26. Treatment of Chronic ITP (II) • Intravenous immunoglobulin (IVIG): The mechanism of action is probably blockade of the reticuloendothelial system, preventing phagocytosis of platelets • The dose is 0.5 to 1 g/kg daily for 2 or 3 days, repeated every 10 to 21 days as needed • The platelet count usually begins to rise within 2 to 4 days • Intravenous immunoglobulin is well tolerated but very expensive • Anti-Rho (D) antibody (WinRho SDF): WinRho SDF is a polyclonal antibody preparation against the Rho (D) red cell antigen, which may be useful in Rho (D)-positive patients (~85% of the population). Approximately 50% of patients respond to this treatment

27. Treatment of Chronic ITP (III) • Splenectomy: Splenectomy removes the primary site of platelet destruction and also a site of antibody production. • Approximately 65% of patients have a complete response, and an additional 15% have a partial response. 15% of responders relapse. • The main side effect of splenectomy is the risk of overwhelming sepsis • Other therapies: Other therapies that are used in refractory patients, or those that relapse after splenectomy, include vincristine, cyclophosphamide, other cytotoxic agents, and danazol. ➪It is wise to anticipate the eventual need for splenectomy in most adult patients and prepare for it by vaccinating patients against Streptococcus pneumoniae, Haemophilus influenzae, and meningococcus as soon as the diagnosis of ITP is made.

28. Treatment of Chronic ITP (IV) • Rituximab is another second-line treatment to be considered after failure of initial glucocorticoid treatment, and has at least short-term effectiveness in about 40 percent of patients with ITP • Combination with dexamethasone is also possible • Rituximab has also been documented to be effective in both adults and children who have failed to respond to splenectomy • Dose: four weekly intravenous injections of rituximab (375 mg/m2 per dose) • Progressive multifocal leukoencephalopathy is the most critical long-term adverse effect of Rituximab

29. Treatment of Chronic ITP (V) • Thrombopoiesis-stimulating agents (TPO mimetics, thrombopoietin receptor agonists) are approved by the United States FDA for use in ITP in adults "with insufficient response to corticosteroids, immunoglobulins, or splenectomy", and have been advocated for second-line treatment of ITP • The use of thrombopoiesis-stimulating agents as second-line treatment is not recommended until other treatments to achieve a durable remission have failed • Thrombopoiesis-stimulating agents are expensive, only support an increased platelet count as long as they are continued, do not induce a remission, and their long-term side effects are not fully known • European medicines evaluation agency (EMA), which has approved these agents for "splenectomized adults who are refractory to other treatments."

30. Qualitative Disorders of Platelet

31. Inherited qualitative disorders of platelet • Glanzmann thrombasthenia is characterized by severely reduced or absent platelet aggregation in response to multiple physiologic agonists because of qualitative or quantitative abnormalities of platelet glycoprotein IIb (GPIIb; CD 41) and/or 3 (GPIIIa; CD61). • Abnormalities in the receptor result in a failure of platelet plug formation at sites of vascular injury, leading to excessive bleeding and bruising. • Platelet transfusion is the mainstay of therapy for serious bleeding in Glanzmann thrombasthenia and as prophylaxis prior to surgery or other major hemostatic stresses.

32. Inherited qualitative disorders of platelet • Bernard-Soulier syndrome is an inherited disorder of the platelet GPIb-IX-V complex characterized by thrombocytopenia, giant platelets, and a failure of platelets to bind GPIb ligands, most importantly, von Willebrand factor and thrombin. • The platelet GPIb-IX complex functions as a receptor for von Willebrand factor. This interaction is crucial for the adhesion of platelets to subendothelial surfaces, especially under high shear conditions, where von Willebrand factor acts as a bridge between the subendothelial matrix and the platelet. • Platelet alpha or delta granule defects or release defects

33. Acquired qualitative disorders of platelet • Hematologic diseases • Myeloproliferative disorders • Acute leukemias • Myelodysplastic syndromes • Dysproteinemias • Multiple myeloma • Waldenström macroglobulinemia • Acquired von Willebrand disease • Drugs • Aspirin • NSAIDs • Antibiotics

34. Systemic Disorders Associated with Abnormal Platelet Function • Uremia • Anemia • Toxic metabolites • Cardiopulmonary bypass