Immune thrombocytopenic purpura or ITP: It is an acquired thrombocytopenia caused by destruction of platelets by antiplatelet antibodies. Antibodies in ITP may also inhibit the maturation and differentiation of megakaryocyte precursors to megakaryocytes. Hence, platelet production in bone marrow decreases. It may be primary or idiopathic, or secondary to autoimmune diseases like SLE, infections like HIV, Hep C, H.pylori, CMV, infectious mononucleosis, drugs like quinine, abciximab, tirofiban, eptifibatide, acetaminophen, carbamazepine, trimethoprim/sulfamethoxazole, chlorpropamide, certain foods like tahini, herbal remedies like herbal teas etc. Drug induced ITP or DITP can occur as an idiosyncratic reaction. Antibodies bind to platelet membrane glycoproteins such as GP IIb-IIIa or GP Ib-V-IX. DITP resolves after discontinuation of the offending drug. ITP clinically manifests as purpura, petechial hemorrhages, easy bruising, epistaxis, menorrhagia, bleeding from gums, haematuria, ICH etc. Hepatosplenomegaly may be seen. Laboratory findings include reduced platelet count, antiplatelet IgG may be positive, decreased platelet survival and bone marrow may show increased or decreased megakaryocytes. Most patients with ITP recover spontaneously. Platelet transfusions can be used in acute bleeding episodes. Corticosteroids, vincristine, cyclophosphamide, mycophenolate mofetil or azathioprine can be used. Newer agents include thrombopoietin, romiplostim, eltrombopag, rituximab, rapamycin (Sirolimus), fostamatinib (inhibitor of spleen tyrosine kinase), FcRn (neonatal Fc receptor) antagonists and BTK (Bruton tyrosine kinase) inhibitors . Splenectomy is reserved for resistant cases.
Thrombotic thrombocytopenic purpura (TTP) and Hemolytic uremic syndrome (HUS): HUS and TTP are characterized by the triad of microangiopathic anemia with red blood cell fragmentation, thrombocytopenia and acute renal failure. TTP has the same three features plus the presence of fever and neurological symptoms, creating a pentad. Basic pathology is damage to endothelial cells and microthrombi. Other symptoms include weakness, fatigue, pallor, petechiae, purpura and bleeding.
HUS often follows infections by E.coli O157:H7 (foodborne) or Shiga toxin (Stx) producing E.coli, like diarrhea or colitis. Patients present with bloody diarrhea, followed a few days later by HUS. Stx enters the bloodstream from the gastrointestinal tract. It then binds to a glycosphingolipid Gb3 on glomerular endothelial cells, podocytes, mesangial cells, tubular epithelial cells and other endothelial cells. It inhibits protein synthesis, increases release of cytokine IL8, increases endothelial cell expression of CXCR4 and induces complement.
Some cases of HUS are not due to Stx but may be seen due to genetic or acquired causes and is called “aHUS or atypical HUS”. aHUS may become chronic with recurrent relapses. It is caused by abnormal and excessive activation of the alternate pathway of complement. It may follow an URTI or gastroenteritis in children, commonly following pneumococcal infections. In familial aHUS, there are mutations in genes regulating the alternate complement pathway, like MCP or factor I.
Secondary HUS is seen in malignancy, HIV, histoplasmosis, Coxsackie virus, Mycoplasma pneumoniae, organ or bone marrow transplants, autoimmune disorders like SLE and antiphospholipid syndrome, and drugs like cyclosporine, tacrolimus, ticlopidine, clopidogrel, chemotherapeutic agents, bevacizumab etc.
TTP is caused by congenital or acquired reductions in metalloprotease enzyme ADAMTS13 activity. The defect causes persistence of ultra large multimers of vWF that are hyperactive in binding the platelet receptor GPIb-IX-V complex, which results in spontaneous platelet aggregation and widespread thrombosis. Acquired cases are seen in SLE, malignancy, cryoglobulinemia, pregnancy, antiphospholipid syndrome, chemotherapy and drugs like clopidogrel, ticlopidine and antiarrhythmics.
Diagnosis is by clinical features and confirmed by laboratory findings of thrombocytopenia, microangiopathic hemolytic anemia showing schistocytes or helmet cells, elevated LDH, negative Coombs test, normal values for PT/INR, PTT and fibrinogen; D dimer may be positive, complement levels may be low in aHUS. Serum creatinine and BUN will be high from renal failure. Stool culture, assay for Stx in stool, PCR for ST1 and ST2 in stool and antibody detection by serological tests are used for diagnosis of Stx-HUS. Assays for level and activity of the enzyme ADAMTS13 are done to diagnose TTP.
Treatment is mainly supportive. Eculizumab, a monoclonal antibody to C5a, has been found useful in the treatment of Stx-HUS and aHUS. Patients with TTP respond well to plasmapheresis, corticosteroids, vincristine, azathioprine, cyclophosphamide, IV IgG, rituximab, prostacyclin and splenectomy. Antibiotics should be avoided in the treatment of Stx-HUS.
HELLP Syndrome: It is characterized by hemolysis, elevated liver enzymes and low platelet count (Hemolysis-Liver-LowPlatelets) and is seen in pregnancy. Pre-eclampsia is pathophysiologically similar, only milder. HELLP syndrome develops most commonly in pregnant women with eclampsia and preeclampsia. Rarely, mothers of fetuses with LCHAD deficiency or long-chain 3 hydroxyacyl-CoA dehydrogenase deficiency may develop HELLP syndrome. Symptoms include fatigue, malaise, excess weight gain, fluid retention, headache, abdominal pain, epistaxis, blurry vision and seizures. Patients may develop complications like ARDS, pulmonary edema, placental abruption, DIC, sepsis and renal failure. HELLP syndrome is associated with high maternal and infant mortality. Laboratory findings include low platelet count, elevated liver enzymes, low hematocrit, decreased or absent serum haptoglobin, elevated LDH, positive D-dimer and normal PT, PTT and fibrinogen (except in the presence of DIC). High levels of circulating soluble VEGF receptor (sFlt1) are seen. Treatment is with dexamethasone, magnesium sulphate, antihypertensives (hydralazine, labetalol, nifedipine, sodium nitroprusside or nitroglycerine), supportive therapy, plasmapheresis and termination of pregnancy in unstable patients.
DIC: DIC or disseminated intravascular coagulation is characterized by widespread activation of coagulation resulting in microthrombi formation, multiple organ failure and bleeding from consumptive coagulopathy and hyperfibrinolysis.
Causes of DIC
Sepsis, trauma, abruptio placentae, amniotic fluid embolism, IUD, surgery, HUS, TTP, severe burns, aortic aneurysm, malignancies, snake bite, heat stroke, hepatic failure etc.
Bleeding dominant DIC is seen in leukemias especially acute promyelocytic leukemia, obstetric conditions like abruptio placentae and aortic aneurysms. Organ failure or hypercoagulative type of DIC is seen in sepsis and infections. It results from increased plasminogen activator inhibitor (PAI-I) levels due to cytokines and bacterial lipopolysaccharides. Sometimes, both pro and anticoagulant pathways are exaggerated leading to massive bleeding and is often seen post-surgery and in obstetric cases. Laboratory findings include prolonged PT and APTT, decreased platelet count, decreased fibrinogen levels, elevated D-dimer and FDPs or fibrin degradation products and soluble fibrin, decreased antithrombin, protein C, ADAMTS13, elevated thrombomodulin, PAI-I and vWF propeptide. APTT shows a characteristic biphasic waveform with a decrease in light transmittance before clot formation in coagulation assays and is seen at or few hours before the onset of DIC. Treatment is by supportive therapy and by treatment of the underlying disorder causing DIC.
Bernard-Soulier syndrome: It is an AR inherited platelet disorder characterized by dysfunction of the platelet glycoprotein receptor GpIb-V-IX that binds to vWF. It is caused by mutations in the genes GPIBA, GPIBB and GP9. Clinical features include purpura, easy bruising, epistaxis, menorrhagia, bleeding gums, gastrointestinal bleeding and excessive bleeding after trauma or surgery. Laboratory findings include prolonged BT or bleeding time, large platelets, decreased platelet count, flow cytometry detects decreased expression of GpIb receptor while molecular genetic testing can identify relevant mutations. Negative RIPA and presence of aggregation on ristocetin cofactor assay is seen in Bernard-Soulier disease. Aspirin should be avoided.
Glanzmann thrombasthenia: It is an AR inherited platelet disorder caused by defective platelet integrin receptors GpIIb or GpIIIa. Mutations in genes ITGA2B and ITGB3 are seen. The defect interferes with platelet aggregation and platelet plug formation. It presents at birth or in the newborn period with easy bruising and bleeding, epistaxis, bleeding gums, gastrointestinal bleeding, purpura, menorrhagia, hematuria and increased bleeding during surgery. BT is prolonged, platelet count is normal, abnormal platelet aggregation studies, flow cytometry and molecular genetic testing.
