Immune thrombocytopenic purpura (ITP): ITP is an acquired thrombocytopenia caused by immune-mediated platelet destruction due to antiplatelet antibodies. In ITP, antibodies may also inhibit the maturation and differentiation of megakaryocyte precursors into megakaryocytes, which decreases platelet production in the bone marrow.
ITP may be:
Drug-induced ITP (DITP) can occur as an idiosyncratic reaction. In ITP/DITP, antibodies bind platelet membrane glycoproteins such as GP IIb-IIIa or GP Ib-V-IX. DITP typically resolves after discontinuation of the offending drug.
ITP commonly presents with mucocutaneous bleeding, including 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; platelet survival is decreased; and bone marrow may show increased or decreased megakaryocytes.
Most patients with ITP recover spontaneously. Platelet transfusions can be used in acute bleeding episodes. Medications used include corticosteroids, vincristine, cyclophosphamide, mycophenolate mofetil, or azathioprine. 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:
TTP has the same three features plus fever and neurological symptoms, forming a pentad. The basic pathology is endothelial cell damage with microthrombi formation. Other symptoms include weakness, fatigue, pallor, petechiae, purpura, and bleeding.
HUS often follows infection with E.coli O157:H7 (foodborne) or other Shiga toxin (Stx)-producing E.coli, typically presenting as diarrhea or colitis. Patients may develop bloody diarrhea, followed a few days later by HUS.
Pathogenesis in Stx-HUS:
Some cases of HUS are not due to Stx and are termed “aHUS” (atypical HUS). aHUS may become chronic with recurrent relapses. It is caused by abnormal and excessive activation of the alternate complement pathway. It may follow an URTI or gastroenteritis in children, commonly after pneumococcal infections. In familial aHUS, mutations occur in genes regulating the alternate complement pathway, such as 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 such as cyclosporine, tacrolimus, ticlopidine, clopidogrel, chemotherapeutic agents, bevacizumab, etc.
TTP is caused by congenital or acquired reductions in the activity of the metalloprotease enzyme ADAMTS13. This defect leads to persistence of ultra large vWF multimers that are hyperactive in binding the platelet receptor GPIb-IX-V complex, resulting in spontaneous platelet aggregation and widespread thrombosis. Acquired cases are seen in SLE, malignancy, cryoglobulinemia, pregnancy, antiphospholipid syndrome, chemotherapy, and drugs such as clopidogrel, ticlopidine, and antiarrhythmics.
Diagnosis is based on clinical features and supported by laboratory findings, including thrombocytopenia and microangiopathic hemolytic anemia with schistocytes or helmet cells. Typical lab findings include elevated LDH, a negative Coombs test, and normal PT/INR, PTT, and fibrinogen. D dimer may be positive. Complement levels may be low in aHUS. Serum creatinine and BUN are elevated due to renal failure.
For Stx-HUS, diagnostic tests include stool culture, stool assay for Stx, PCR for ST1 and ST2 in stool, and antibody detection by serological tests. For TTP, assays measuring ADAMTS13 level and activity are used.
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: HELLP syndrome is characterized by hemolysis, elevated liver enzymes, and low platelet count (Hemolysis-Liver-LowPlatelets) and is seen in pregnancy. Pre-eclampsia is pathophysiologically similar but milder. HELLP syndrome develops most commonly in pregnant women with eclampsia and preeclampsia. Rarely, mothers of fetuses with LCHAD deficiency (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. Complications may include 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 includes dexamethasone, magnesium sulphate, antihypertensives (hydralazine, labetalol, nifedipine, sodium nitroprusside, or nitroglycerine), supportive therapy, plasmapheresis, and termination of pregnancy in unstable patients.
DIC: DIC (disseminated intravascular coagulation) is characterized by widespread activation of coagulation, leading to microthrombi formation, multiple organ failure, and bleeding due to consumptive coagulopathy and hyperfibrinolysis.
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 such as abruptio placentae, and aortic aneurysms. Organ failure (hypercoagulable) type 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 procoagulant and anticoagulant pathways are exaggerated, leading to massive bleeding; this 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 (fibrin degradation products) and soluble fibrin, decreased antithrombin, protein C, and ADAMTS13, and elevated thrombomodulin, PAI-I, and vWF propeptide. APTT may show a characteristic biphasic waveform, with a decrease in light transmittance before clot formation in coagulation assays; this can be seen at or a few hours before the onset of DIC.
Treatment is supportive and includes treating the underlying disorder causing DIC.
Bernard-Soulier syndrome: Bernard-Soulier syndrome is an AR inherited platelet disorder characterized by dysfunction of the platelet glycoprotein receptor GpIb-V-IX, which 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 (bleeding time), large platelets, and decreased platelet count. Flow cytometry detects decreased expression of the 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: Glanzmann thrombasthenia is an AR inherited platelet disorder caused by defective platelet integrin receptors GpIIb or GpIIIa. Mutations in genes ITGA2B and ITGB3 are seen. This 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, and platelet aggregation studies are abnormal. Flow cytometry and molecular genetic testing may be used.
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