Drug induced thrombocytopenia

• Thrombocytopenia develops 1-2 weeks after exposure to drug/ herbal medicine.
• Thrombocytopenia is usually severe
• Mechanism of development of thrombocytopenia
  • Immune destruction of platelets- 
    • Hapten dependent antibodies: Penicillin, some cephalosporines, vancomycin
    • Quinine type drug (drug induces antibody that binds to membrane protein in presence of soluble drug)- Quinine, sulphonamide,  NSAIDs
    • Fiban type drug: Drug reacts with glycoprotein IIb/IIIa to induce conformational change which is recognized by antibody- Tirofiban, eptifibatide
    • Drug specific antibody- Antibody recognizes murine component of chimeric Fab fragment specific for platelet membrane glycoprotein IIIa- abciximab
    • Drug induces antibodies that reacts with platelets- gold, procainamide
    • Immune complex formation- Heparin
  • Dose dependent myelosuppression (toxic effect on megakaryocytes)- Chemotherapy medications, interferon alpha, linezolid, bortezomib, thiazide diuretics, ethanol, ganciclovir
  • Antibody independent proapoptotic effect: Tamoxifen, navitoclax, Methotrexate, doxorubicin, ATO, Aspirin, carmustine, cisplatin
  • Drug induced thrombotic microangiopathies- Ticlopidine, clopidogrel, simvastatin
  • Drug hypersensitivity reaction- Allopurinol, isoniazid, sulfasalazine, phenothiazine
• Temporal association between administration drug and occurrence of thrombocytopenia is diagnostic of DITP.
• Treatment
  • Withdrawal of offending drug. 
  • Platelet transfusionsif platelet count is too low
  • IVIg/ steroids may be required in some immune mediated cases
  • Culprit drug should be added to patient’s allergy list.

Thrombocytopenia associated with massive transfusions

• Occurs generally after transfusion of more than 15 PCVs within 24hrs
• Severity of thrombocytopenia varies
• Fibrinogen deficiency develops earlier than thrombocytopenia
• DIC triggered by the disease responsible for blood loss may contribute to thrombocytopenia
• Treatment- FFPs followed by platelet transfusions

Thrombocytopenia resulting from hypothermia

• Occurs when body temperature is less than 25 degree C
• Degree of thrombocytopenia correlates with degree of drop in temperature
• Drop in temperature leads to clustering of GpIb complex and rearrangement of its carbohydrate chains, which leads to enhanced phagocytosis of platelets by macrophages.

Post-transfusion purpura

Introduction:

• It is a rare thrombocytopenic syndrome that is provoked by an alloimmune response against human platelet antigens, most frequently HPA-1a 

Epidemiology:

• M:F- 1:5
• 1-2/ 1lac transfusions
• Incidence decreases with use of leucocyte filters

Etio-pathogenesis:

Prior sensitization to platelet antigens during pregnancy/ transfusion

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Upon resensitization, patients develop potent antibodies against platelet specific antigens

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Fixation of complements

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Destruction of both transfused and patient's platelets

(By mechanism of "innocent bystander- epitope spreading" which is poorly understood)

Clinical Features:

• Symptoms are seen 5-10 days post transfusion and resolves within weeks
• Bleeding- Petechiae, purpura, mucosal hemorrhage, hematuria, intracranial bleed
• Thrombocytopenia is refractory to platelet transfusions 

Investigations:

• Patients' platelet genotyping- Usually HPA-1bb genotype
• Detection of Anti-HPA-1a antibodies 

Criteria for Diagnosis:

• Temporal association between transfusion and platelet drop suggests diagnosis 

Treatment: Start treatment even before serology test results are available

• High dose IVIg
• High dose steroids
• Transfusion of HPA-1a negative platelets
• Plasma exchange, if there is no response to IVIg 

Post surgery thrombocytopenia

• 30%-70% decline in platelet count is seen universally after all major surgeries
• Mechanisms
  • Hemodilution
  • Increased platelet consumption
• Fall in platelet count is abrupt and is seen evident few hours after surgery.
• Peak rise in platelet count is seen at 14 days and returns to baseline in next 2 weeks

Chemotherapy/ Radiotherapy related thrombocytopenia

• Prompt recovery is often seen

Cyclic thrombocytopenia

• Periodic thrombocytopenia and thrombocytosis
• Each cycle spans about 3-6 weeks
• Common in women
• Pathogenesis is not known
• May have bleeding manifestations
• Generally diagnosed as ITP
• Responds to hormone therapy and cyclosporine

Thrombocytopenia related to splenomegaly

• Bleeding is associated with coagulation defect
• No treatment is required as thrombocytopenia is due to pooling of platelets into spleen and redistribution occurs whenever there is loss of platelets
• Platelet count of less than 20,000/cmm, suggests alternate diagnosis

Gestational thrombocytopenia

• Generally occurs in the 2^nd trimester
• Seen in 4-12% of pregnancies
• Accounts for 70-80% of thrombocytopenia in pregnancy
• Mechanisms
  • Hemodilution
  • Compensated state of subclinical coagulopathy
  • Endothelial injury
  • Immune destruction
  • Platelet consumption by placenta
  • Hormonal depression of megakaryocytes
• Patient is asymptomatic
• Typically, platelet count does not decrease below 70,000/cmm
• Platelet count normalizes within 3 months of delivery
• Epidural anesthesia is safe, if platelet count is >80,000/cmm
• There is no confirmatory test. It is a diagnosis of exclusion.
• Differentiating from ITP is difficult. It is likely to be ITP if,
  • Previous history of ITP
  • Platelet count <50,000/cmm
  • Associated with bleeding
• BMA does not differentiate it from ITP
• Differentiating from ITP is necessary, as antiplatelet antibodies decrease fetal platelet count
• No treatment is required, but monitor CBC once in 2-4 weeks
• If platelet count drops to less than 30,000/cmm, treat like ITP.

Acquired Amegakaryocytic Thrombocytopenia

(For Congenital Amegakaryocytic Thrombocytopenia: Refer Congenital Thormbocytopenia section)

Introduction:

• Characterized by thrombocytopenia with diminished or absent megakaryocytes without additional bone marrow abnormalities.
• Often misdiagnosed as ITP

Epidemiology:

• Very rare condition (So far around 100 cases reported)
• Common in females aged between 40 to 60 years

Etiology:

• Viral infections: Ebstein-Barr virus, parvovirus B19, hepatitis C virus, HIV, and cytomegalovirus
• Drugs and toxins: Interferon therapy, radioiodine therapy, benzene exposure, alcohol use disorder
• Vitamin B12 deficiency, PNH
• Idiopathic/ Immune(As there is high association with thymoma and other autoimmune disorders such as SLE and systemic sclerosis): 
  • Suppression of megakaryocyte maturation by antibody-mediated mechanism (anti-c-Mpl antibodies that bind to the thrombopoietin receptor) 
  • T-cell autoimmunity 
• Precursor of other hematological diseases such as AML, MDS, Aplastic anemia etc.

Clinical features:

• Bleeding manifestations: Mostly mucosal
• Presence of lymphadenopathy/ splenomegaly indicate alternate diagnosis

Investigations:

• CBC: Thrombocytopenia. Rest of parameters are usually normal
• BMA and Biopsy: 
  • Normal overall cellularity with a reduction or absence of megakaryocytes
  • Megakaryocytes may look immature or small, with no evidence of dysplasia
  • Late stages may show hypocellular BM indicating progression to aplastic anemia
• LFT, PT and APTT: To look for features of hepatic dysfunction
• HIV and HCV
• ANA
• APLA work up

Prognosis:

• Variable
• Progression to aplastic anemia/ MDS/ AML carries poor prognosis

Treatment:

• Currently no established treatment guidelines due to rarity of disease
• Treatment of underlying cause if found
• Idiopathic cases:
  • Cyclosporine: Dose: 6 mg/kg/day, adjusted to maintain trough levels between 150 and 300 ng/mL. 
  • Prednisone: Dose: 40-60 mg/Day. Durable response is rare. Those secondary to SLE usually respond.
  • Eltrombopag/ Romiplostim
  • Antithymocyte globulin: ATG at a dose of 40 mg/kg/day for four days and then an extended course of cyclosporine. Useful even in patients who have progressed to aplastic anemia.
  • Rituximab
  • Other less commonly used options include: MMF, Cyclophosphamide,  Danazol, Azathioprine, Plasmapheresis, High dose IVIg, Alemtuzumab
  • Bone marrow transplant: If above measures fail.