Thrombotic thrombocytopenic purpura and pregnancy

Thrombotic thrombocytopenic purpura (TTP) is an acute life threatening disorder associated with a deficiency in the enzyme ADAMTS 13. It is diagnosed by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and widespread microvascular thrombosis resulting in organ ischaemia. Approximately 70% of TTP cases occur in women and nearly half of these women are of childbearing age. Pregnancy is a recognised precipitating cause of TTP in between 10‐25% of all cases and includes patients with acquired antibody mediated TTP and congenital TTP, often presenting in adult hood. The availability of ADAMTS 13 assays allows differentiation between congenital and acquired TTP and appropriate treatment plans. There is also a subsequent risk of TTP relapse in women with previous non‐pregnancy related TTP. Presentation may occur at any stage in pregnancy or in the post partum period. This would suggest an hormonal influence as well as the reduction in ADAMTS 13 from the second trimester, related to pregnancy associated increase in Von Willebrand Factor. Differentiation from other pregnancy associated microangiopathies, such as pre‐eclampsia, HELLP (haemolysis, elevated liver enzymes and low platelets) or HUS (haemolytic Uraemic Syndrome) may be clinically difficult, but necessary, in part, because of differences in treatment. HELLP and pre‐eclampsia require delivery and HUS supportive care. TTP requires urgent treatment with plasma exchange (PEX) to attain remission, but also to prevent fetal abnormalities resulting from placental thrombosis. Presented is a review of the literature of pregnancy associated TTP and our experience of treatment of patients who present with TTP during pregnancy and monitoring of women who have had a history of TTP. Positive outcome in pregnancy has been associated with regular monitoring of routine laboratory parameters and ADAMTS 13 activity. All patients maintain low dose aspirin therapy and low molecular weight heparin is started in those women where an increased thrombotic risk is determined. The aim is to optimise implantation and preservation of placental function, especially in women with previous pregnancy loss, as abnormalities of the uteroplacental circulation resulting in insufficiency are established early in the first trimester. A significant reduction in ADAMTS 13 activity or reduction in platelet count below the normal range, PEX is undertaken to prevent any further deterioration. Frank relapse is treated with daily PEX. In women with a congenital TTP phenotype, regular treatment through pregnancy has been successfully undertaken. It is very difficult to devise evidence based guidelines for pregnancy in women with a history of TTP. In our cohort, patients with ADAMTS 13 activity < 5% at presentation in the current pregnancy had a history of TTP precipitated during pregnancy or recurrent TTP episodes, such that the chance of further exacerbation during pregnancy was considered to be high. Indeed, cases 1, 2 and 4 have demonstrated ADAMTS 13 activity < 5% before and after these pregnancies and only case 3 and 5 had further TTP episodes following pregnancy. Therefore the intensive monitoring and treatment was based on the high probability of relapse during pregnancy. Indeed, in Patients with normal ADAMTS 13 activity at the start of pregnancy were continually monitored, but did not have a TTP relapse. In Conclusion: a multidisciplinary approach to pregnancy care with regular monitoring of routine laboratory parameters and ADAMTS 13 activity during pregnancy allows pre‐emptive treatment of patients who are at risk from TTP relapse.     

Thrombotic thrombocytopenic purpura: treatment with a combination of antiplatelet drugs

Thrombotic thrombocytopenic purpura (TTP) is a rare disease with a vary high mortality. Different modalities of therapy have been tried, but often with no effect. Recently, interest has focused on drugs interfering with platelet function, though few patients have received antiplatelet drugs as the only therapy. We describe a patient with TTP, who recovered completely on a combination therapy with dextran, aspirin and dipyridamole.     

Thrombotic thrombocytopenic purpura associated with clopidogrel

BACKGROUND: The antiplatelet drug clopidogrel is a new thienopyridine derivative whose mechanism of action and chemical structure are similar to those of ticlopidine. The estimated incidence of ticlopidine-associated thrombotic thrombocytopenic purpura is 1 per 1600 to 5000 patients treated, whereas no clopidogrel-associated cases were observed among 20,000 closely monitored patients treated in phase 3 clinical trials and cohort studies. Because of the association between ticlopidine use and thrombotic thrombocytopenic purpura and other adverse effects, clopidogrel has largely replaced ticlopidine in clinical practice. More than 3 million patients have received clopidogrel. We report the clinical and laboratory findings in 11 patients in whom thrombotic thrombocytopenic purpura developed during or soon after treatment with clopidogrel. METHODS: The 11 patients were identified by active surveillance by the medical directors of blood banks (3 patients), hematologists (6), and the manufacturer of clopidogrel (2). RESULTS: Ten of the 11 patients received clopidogrel for 14 days or less before the onset of thrombotic thrombocytopenic purpura. Although 10 of the 11 patients had a response to plasma exchange, 2 required 20 or more exchanges before clinical improvement occurred, and 2 had relapses while not receiving clopidogrel. One patient died despite undergoing plasma exchange soon after diagnosis. CONCLUSIONS: Thrombotic thrombocytopenic purpura can occur after the initiation of clopidogrel therapy, often within the first two weeks of treatment. Physicians should be aware of the possibility of this syndrome when initiating clopidogrel treatment.     

Thrombotic thrombocytopenic purpura in children]

An analysis of 4 cases of the thrombotic thrombocytopenia in children of 4 to 10 years of age is performed. The disease was characterized by fever, purpura, headache and abdominal pains, arterial hypertension, microangiopathic haemolytic anemia, thrombocytopenia, increase of blood urea and serum creatinine, micro-haematuria and proteinuria. The duration of the disease was from 4 days to 7 months. Anuria, gangrene of the ears, scrotum, penis and soft tissues of legs and feet were registered in a 5-year-old patient with a fulminant disease. The cause of death of other patients was heart failure with acute lung oedema, brain haemorrhages and haemorrhagic pancreonecrosis. The diagnosis of the thrombotic thrombocytopenia was confirmed by the finding in the autopsy material of thrombotic microangiopathy of small arteries, veins, arterioles, venules and capillaries in kidneys and other organs and tissues. Kidney damage in fulminant disease is complicated by segmentary cortical necrosis, in a more prolonged disease--by glomerulosclerosis or mesangio-capillary glomerulonephritis.     

Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome

OBJECTIVE: To evaluate the usefulness and feasibility of measuring plasma von Willebrand factor (vWF)-cleaving metalloprotease activity (ADAMTS 13) in the differential diagnosis of thrombotic thrombocytopenic purpura (TTP), the hemolytic uremic syndrome, and other thrombotic microangiopathies. DATA SOURCES: Articles published in the medical literature. DATA EXTRACTION AND SYNTHESIS: In TTP, a multimeric form of vWF that is larger than that ordinarily found in the plasma may cause systemic platelet aggregation under the high-shear conditions of the microcirculation. ADAMTS 13 is a divalent cation-activated, vWF-cleaving metalloprotease that converts unusually large vWF multimers derived from endothelial cells into smaller vWF forms in normal plasma. ADAMTS 13 is severely reduced or absent in most patients with TTP. The vWF-cleaving metalloprotease is present in fresh-frozen plasma, cryoprecipitate-depleted plasma (cryosupernatant), and in plasma that has been treated with solvent and detergent. The enzyme is defective in children with chronic relapsing TTP. Infusion of any of the plasma products that contain the vWF-cleaving metalloprotease stops or prevents (for about 3 weeks) TTP episodes in these patients. An immunoglobulin (Ig) G autoantibody to the vWF-cleaving metalloprotease is found transiently in many adult patients with acquired acute idiopathic, recurrent, and ticlopidine/clopidogrel-associated TTP. Patients with acquired TTP require plasma exchange, that is, both infusion of a plasma product containing vWF-cleaving metalloprotease and removal of autoantibody and/or unusually large vWF multimers by plasmapheresis. The pathophysiology of platelet aggregation in bone marrow transplantation/chemotherapy-associated thrombotic microangiopathy, as well as in hemolytic uremic syndrome, is not established. In neither condition is there a severe decrease in plasma vWF-cleaving metalloprotease activity, as there is in TTP. CONCLUSIONS: The presently available lengthy and complicated procedure for estimation of plasma vWF-cleaving metalloprotease activity is not yet practical for rapid diagnostic use. This test has supplanted the equally lengthy and difficult, less specific analysis of plasma vWF multimeric pattern. If the clinical distinction between TTP and hemolytic uremic syndrome is uncertain, it is appropriate to acquire (before therapy) a citrate-plasma sample for the ultimate determination of vWF-cleaving metalloprotease activity.     

Thrombotic thrombocytopenic purpura: a case report

We report a case of thrombotic thrombocytopenic purpura (TTP) in a 60 years-old woman with Sjogren's syndrome. Symptomatology on admission leads to evoke the diagnosis of TTP. Biological results allow to set the diagnosis. Actually, association of haemolytic anaemia, schizocytes and thrombocytopenia are in favour of TTP. Undetectable ADAMTS 13 activity (below 5%) confirms the diagnosis. In congenital TTP, plasma ADAMTS 13 is absent or severely reduced as a consequence of mutations in the two ADAMTS 13 gene. In acquired TTP, circulating antibodies inhibit plasma ADAMTS 13 activity. In those cases, further biological studies are needed to find a cause of TTP. Follow-up implies standard laboratory tests. Plasma exchanges are progressively tapered after normalization of platelets count.     

Thrombotic thrombocytopenic purpura in a child with Alexander's disease

Thrombocytopenic purpura developed in a 14-year-old boy with Alexander's disease; he died. The proximity of Rosenthal fibers to small vessels in the brain, the presence of perivascular lymphocytes in the brain, and the presence of complement in renal arterioles suggest that the Rosenthal fibers could have injured the endothelium-basement membrane resulting in an immune response triggering the thrombotic thrombocytopenic purpura.     

血栓性血小板减少性紫癜:一例尸检分析

死者女,48岁.因右下腹疼痛6 d,全身多处淤点、淤斑,多次发生晕厥、全身抽搐,意识不清1 d于2005年1月21日入当地医院,入院后行阑尾切除术.术后1 h出现阴道流血,较平时月经量多1倍以上.     

Thrombotic thrombocytopenic purpura-like syndrome associated with systemic lupus erythematosus--combined treatment with plasmapheresis and fresh frozen plasma infusion.

We report on a patient with systemic lupus erythematosus, who, during the course of the illness, developed thrombotic thrombocytopenic purpura. In this case, the coexistence of these two conditions was confirmed by laboratory and pathologic findings. The infusion of fresh frozen plasma with plasmapheresis reversed the course of thrombotic thrombocytopenic purpura.     

Thrombotic thrombocytopenic purpura and focal segmental glomerulosclerosis associated with the use of ecstasy

Ecstasy is a drug, which causes serious side effects and sometimes it can be lethal. These effects are due to idiosyncratic reactions as a result of various stimulations in adrenergic receptors. Here we present a case of a 36-year-old male patient who was diagnosed with thrombotic thrombocytopenic purpura associated with the use of ecstasy. Plasmapheresis along with methylprednisolone treatment restores patient condition to normal.     

Thrombotic thrombocytopenic purpura and other thrombotic microangiopathic hemolytic anemias: Diagnosis and classification

Thrombotic microangiopathies (TMAs) include several diseases, most prominently are thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS). TMAs are characterized by profound thrombocytopenia, microangiopathic hemolytic anemia and organ ischemia. In most cases TTP results from deficiency of ADAMTS13, the von Willebrand factor-cleaving protease leading to increase of ultra-large von Willebrand factor (ULVWF) multimers. Congenital TTP is due to mutations in the gene of ADAMTS13 whereas acquired TTP is due to production of autoantibodies against ADAMTS13. In both cases severe deficiency of ADAMTS13 exists. However, the presence of ADAMTS13 activity does not rule out TTP. Diagnostic criteria of TTP are based on clinical features of neurologic and renal disfunction along with anemia and thrombocytopenia, low ADAMTS13 activity, and the presence of ULVWF. The standard treatment of TTP includes plasma exchange, protein A immunoabsobtion, immunosuppressive drugs, CD20 antibodies against B cells, and splenectomy. HUS is commonly caused by infection with Shiga-toxin produced by Escherichia coli. HUS is characterized by thrombocytopenia, anemia, renal impairment and diarrhea. Rarely, atypical HUS appears as a consequence of mutations related to the alternative pathway for the compliment system. Plasmapheresis in HUS is not efficient. Alternatively, plasma therapy and in some cases dialysis are used. TMA diseases may be associated with other infections, bone marrow transplantation, pregnancy, systemic vasculitis, and certain drugs.     

Thrombotic thrombocytopenic purpura and the haemolytic-uraemic syndrome: evolving concepts of pathogenesis and therapy

Thrombotic thrombocytopenic purpura (TTP) and the haemolytic-uraemic syndrome (HUS) are caused by platelet thrombi in the microcirculation (i.e. arterioles and capillaries) throughout the body (TTP) or predominantly in the kidneys (HUS). Plasma factors that induce intravascular platelet agglutination have been a focus of investigation into the pathogenesis of these disorders. Von Willebrand factor (vWF) multimeric forms that are larger than those present in normal plasma are found in the plasma of patients with the chronic relapsing form of TTP. These unusually large vWF multimers are similar to those produced by normal human endothelial cells, but never allowed into the normal circulation. Unusually large vWF multimers in chronic relapsing TTP patients are most apparent in plasma during remission. They disappear, presumably in the process of attaching to platelets and inducing the formation of platelet thrombi, during relapses in chronic TTP. The disappearance of the largest plasma vWF multimeric forms during acute episodes of non-relapsing TTP and HUS has also been seen. These syndromes may be the result of damage to systemic or renal endothelial cells. A cofactor which induces the attachment of large vWF multimers to platelets during episodes of TTP has recently been detected, but not yet characterized biochemically. The cryosupernatant (i.e. vWF-depleted) fraction of normal plasma contains an activity that converts, or potentiates the conversion of, unusually large vWF multimers to the somewhat smaller circulating vWF forms as the bloodstream. There is clinical evidence that an autoantibody may prevent the effect of this 'unusually large vWF depolymerase' in some chronic relapsing TTP patients. Transfusions of normal plasma or cryosupernatant as prophylaxis against, or therapy for, episodes of TTP may transiently provide this missing unusually large vWF depolymerase activity, as well as additional plasma proteins to bind and eliminate the vWF cofactor proposed as the inciting agent of TTP episodes. In some patients, partial removal of unusually large vWF multimers (and possibly the inciting vWF cofactor) by plasmapheresis may be required along with the transfusion of normal plasma or cryosupernatant, in order to control in vivo platelet agglutination. Plasma manipulation has greatly improved the survival of patients with relapsing and non-relapsing forms of TTP. Corticosteroids may also be beneficial. The effectiveness of ancillary measures (splenectomy, vinca alkaloids or other immunosuppressive drugs) is not precisely defined. There is no convincing evidence that aspirin, dipyridamole or PGI2 are helpful in TTP.(ABSTRACT TRUNCATED AT 400 WORDS)     

Thrombotic thrombocytopenic purpura and systemic lupus erythematosus: Successful management of a rare presentation

Thrombotic thrombocytopenic purpura (TTP) and systemic lupus erythematosus (SLE) very rarely present simultaneously and pose a diagnostic and therapeutic dilemma to the critical care team. Prompt diagnosis and management with plasma exchange and immunosuppression is life-saving. A patient critically ill with TTP and SLE, successfully managed in the acute period of illness with plasma exchange, steroids and mycophenolate mofetil is described.