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[Liver diseases and hemostasis].

The liver plays a key role in the regulation of hemostasis. By producing most clotting factors and inhibitors, as well as a number of the proteins involved in fibrinolysis, and by clearing from the bloodstream activated enzymes involved in clotting or fibrinolysis, the liver protects against both bleeding and undue activation of coagulation. It follows that liver diseases are commonly responsible for hemostasis abnormalities including decreased production of clotting factors, thrombocytopenia, platelet dysfunction, and increased circulating fibrinolytic activity. With the exception of cholestasis and in the absence of a specific setting such as pregnancy, the abnormalities are the same in all liver diseases, and their severity varies only with the degree of hepatocellular failure. Although liver diseases do not directly cause disseminated intravascular coagulation (DIC), they are a major risk factor for DIC in patients with infection or shock, as well as during pregnancy. In patients with liver diseases, hemostasis tests can be required to evaluate the degree of hepatocellular failure, the severity of hemostasis disorders manifesting as bleeding, or the bleeding risk before an invasive procedure. Prothrombin time determination is usually sufficient to evaluate the degree of hepatocellular failure, although in some cases assays of fibrinogen and factors II, VII, X, V are also useful. Evaluation of the bleeding risk prior to an invasive procedure requires a study of platelet function and measurement of circulating fibrinolytic activity, which is particularly likely to be abnormal in patients with severe hepatocellular failure and/or alcohol abuse. A less common reason for investigating hemostasis is a search for the cause of a thrombotic condition, such as portal vein thrombosis or Budd-Chiari syndrome.

Blood Coagulation Disorders↗

Obstetrical and gynaecological bleeding: a common presenting symptom.

Excessive haemorrhage is one of the commonest symptom when women present to obstetricians and gynaecologists. In the majority of cases the cause is related to the primary obstetric and gynaecological pathology and is easily identified. However, less commonly, the bleeding is unexpected and due to an undiagnosed underlying coagulation defect, the commonest of which is von Willebrand (vWD) disease. Menorrhagia is a common, and may be the only, clinical manifestation of an inherited bleeding disorder. Screening 150 women with menorrhagia, vWD was diagnosed in 13% of patients and other hereditary haemorrhagic disorders in another 4%. Menorrhagia with onset at the menarche was predictive of an inherited bleeding disorder in 65% of vWD and 67% of FXI deficient patients. Therefore, testing for bleeding disorders should be considered in women with menorrhagia especially those with early onset and no obvious pelvic pathology. Childbirth and puerperium present a special risk for excessive haemorrhage. The risk of postpartum haemorrhage is very high in women with inherited bleeding disorders. In our centre, the incidence of primary and secondary postpartum haemorrhage was 22% and 11% in carriers of haemophilia 18.5% and 20% in vWD and 16% and 24% in FXI deficient women, respectively. Acquired haemophilia can be an unusual cause of severe and unexpected postpartum haemorrhage with a very high mortality rate. Unexplained postpartum and postoperative haemorrhage that does not respond to general measures should alert clinicians to the possibility of bleeding disorders as a causative factor. In addition, increased awareness among obstetricians and gynaecologists of these less common causes and close collaboration with the local haemophilia centre and availability of management guidelines are essential for optimal outcome.

Adult↗

Spectrum of inherited bleeding disorders from Western India.

OBJECTIVE: The study was undertaken to assess the magnitude and diversity of different bleeding disorders in Western India. MATERIALS AND METHODS: 768 cases referred to our Institute for evaluation of an underlying bleeding diathesis were investigated appropriately to detect the cause of the abnormal hemostatic function. RESULTS: 630 patients were diagnosed to have hereditary bleeding diathesis. Amongst these, 598 patients had a coagulation disorder while only 32 patients had a platelet function abnormality. Amongst the coagulation disorders, hemophilia A (70.5%) was the most common disorder followed by hemophilia B (14%) and VWD (10.8%). Glanzman's thrombasthenia (84.3%) was the most common platelet function disorder followed by Bernard-Soulier syndrome (12.5%). Some rare disorders have also been diagnosed. CONCLUSION: In spite of their apparent rarity, India has a substantial number of cases of inherited bleeding disorders. A large number of these patients is referred to many tertiary care institutions. It is therefore desirable that district hospitals must develop their laboratories to detect most of these disorders so that the patients need not travel long distances to get an appropriate diagnosis and proper management. All 1st degree female relatives of severe and moderate hemophilia must get factor assays done because some of them may be vulnerable to post-procedural or post-traumatic bleeding.

Blood Coagulation Disorders, Inherited↗

Fibrinogen Alès: a homozygous case of dysfibrinogenemia (gamma-Asp(330)-->Val) characterized by a defective fibrin polymerization site "a".

Congenital homozygous dysfibrinogenemia was diagnosed in a man with a history of 2 thrombotic strokes before age 30. His hemostatic profile was characterized by a dramatically prolonged plasma thrombin clotting time, and no clotting was observed with reptilase. Complete clotting of the abnormal fibrinogen occurred after a prolonged incubation of plasma with thrombin. The release of fibrinopeptides A and B by thrombin and of fibrinopeptide A by reptilase were both normal. Thrombin-induced fibrin polymerization was impaired, and no polymerization occurred with reptilase. The polymerization defect was characterized by a defective site "a," resulting in an absence of interaction between sites A and a, indicated by the lack of fragment D(1) (or fibrinogen) binding to normal fibrin monomers depleted in fibrinopeptide A only (Des-AA fm). By SDS-PAGE, the defect was detected on the gamma-chain and in its fragment D(1). The molecular defect determined by analysis of genomic DNA showed a single base change (A-->T) in exon VIII of the gamma-chain. The resulting change in the amino acid structure is gamma 330 aspartic acid (GAT) --> valine (GTT). It is concluded that the residue gamma-Asp(330) is essential for the normal functioning of the polymerization site a on the fibrinogen gamma-chain.

Adult↗

[Thrombosis of the renal vein and hemorrhagic rectocolitis].

Renal vein thrombosis was observed in a patient with acute ulcerative colitis complicated by retroperitoneal perforation. Retroperitoneal inflammation related to colonic perforation may constitute a predisposing factor for local thrombosis in combination with coagulation disorders (protein S deficiency).

Adult↗

Coagulation and bleeding disorders: review and update.

Hemostasis is initiated by injury to the vascular wall, leading to the deposition of platelets adhering to components of the subendothelium. Platelet adhesion requires the presence of von Willebrand factor and platelet receptors (IIb/IIIa and Ib/IX). Additional platelets are recruited to the site of injury by release of platelet granular contents, including ADP. The "platelet plug" is stabilized by interaction with fibrinogen. In this review, I consider laboratory tests used to evaluate coagulation, including prothrombin time, activated partial thromboplastin time, thrombin time, and platelet count. I discuss hereditary disorders of platelets and/or coagulation proteins that lead to clinical bleeding as well as acquired disorders, including disseminated intravascular coagulation and acquired circulating anticoagulants.

Blood Coagulation Disorders↗

Production and composition of prothrombin complex concentrates: correlation between composition and therapeutic efficiency.

Four-factor PCCs are most frequently used for replacement of vitamin K-dependent clotting factors and inhibitors proteins C and S in patients bleeding after phenprocoumon or warfarin overdose, in vitamin K-deficient patients presenting life-threatening bleeding, and liver disease. Since many of these patients are prone to thromboembolic complications including DIC, all conceivable measures should be taken against the thrombogenic potential of PCC preparations. This thrombogenic potential of PCCs is obviously dependent on several factors including activated clotting factors, lack of inhibitors of blood coagulation, and coagulation factor overload, as well as predisposing factors referred to recipients and drug interactions. The composition of PCC should meet the following criteria: Antithrombin in addition to heparin for the neutralization of FIXa and FXa should be present in the preparations; no overloading with FII and FX; substantially lower FVII than FIX potencies in order to minimize contamination with or generation of FVIIa; and substantial protein C as well as protein S activities. Quality control should include determinations as recommended by the European Pharmacopoeia. Specific assays for quantification of FIXa and FXa are urgently required, and validity of these assays must be proven in surveys. All lots should also be tested for their FVIIa content. Furthermore, the safety of PCCs must be proven by suitable animal models. Whenever possible, patients receiving PCCs should be under low-dose heparin prophylaxis; simultaneous administration of heparin-neutralizing drugs or antifibrinolytic agents must be avoided.

Blood Coagulation Factors↗

Coagulation tests in differential diagnosis.

Bleeding disorders pose a special problem for the practising physician haematologist or laboratory coagulation specialist. Great concern is placed on specimen integrity, either during handling or in storage. Heparin contamination, activated specimens and factor VIII lability are common issues.

Blood Coagulation Disorders↗

Recurrent miscarriage syndrome and infertility caused by blood coagulation protein or platelet defects.

Recurrent miscarriage syndrome and infertility are common problems in the United States. Recurrent miscarriage affects more than 500,000 women annually. If properly screened through a cost-effective protocol, the cause will be found in almost all women. The most common singular defect in women with RMS is a hemostasis defect, and if a thorough APLS evaluation is performed, the most common of these is found to be APLS. Other hereditary and acquired procoagulant defects are also commonly found, if looked for. It is important to evaluate women with RMS appropriately, because if a cause for the RMS is found, most women will achieve normal-term delivery. Hemorrhagic defects are rare hemostasis causes of RMS, but these defects also are treatable in many instances and should be considered in appropriate women. Treatment of the common procoagulant defects consists of preconception low-dose ASA at 81 mg/day followed by immediate postconception low-dose unfractionated porcine heparin. LMWH may be a suitable alternative.

Abortion, Habitual↗

Treatment of inherited coagulation disorders.

Inherited coagulation protein deficiencies associated with bleeding diatheses may present with spontaneous bleeding early in life, or may not be recognized until the development of hemorrhage after trauma or surgery. Diagnostic evaluation with coagulation screening tests, followed by confirmation with coagulation factor assays, is essential for appropriate management. For moderate-to-severe hemophilia, treatment includes coagulation factor replacement with purified, plasma-derived coagulation factor, or in the case of hemophilia A, factor VIII concentrate produced with recombinant techniques. Increased use of pharmacologic agents such as desmopressin acetate for patients with mild hemophilia A or type 1 von Willebrand's disease has allowed physicians to treat patients without the risk of infectious complications from plasma-derived factor concentrates. In addition to the management of the inherited bleeding disorders, patients may also require management of human immunodeficiency virus infection, hepatitis, and coagulation factor inhibitors. Issues for the coming years will include continued work to ensure product safety, the role of prophylactic treatment to prevent longterm disabilities, and the application of gene therapy to the management of bleeding disorders.

Blood Coagulation Disorders↗

Bleeding in a patient with lupus anticoagulant without associated hemostatic abnormalities.

Bleeding is very rare in patients with lupus anticoagulants in the absence of associated hemostatic abnormalities. Few cases have been reported with attention given to work-up for other coagulation defects. We report a case of spontaneous hematoma in a patient with lupus anticoagulant, immunoglobulin (Ig)M anticardiolipin antibodies, and no other associated abnormalities.

Aged↗

Autosomal recessive deficiencies of coagulation factors.

Deficiencies of coagulation factors that cause a bleeding disorder, other than factor VIII and factor IX, are inherited as autosomal recessive traits and are generally rare, with prevalence in the general population varying between 1 in 500 000 and 1 in 2 000 000. In the last few years, the number of patients with recessively transmitted coagulation deficiencies has increased in European countries with a high rate of immigration of Islamic populations where consanguineous marriages are frequent. As a consequence of the relative rarity of these deficiencies, the type and severity of bleeding symptoms, the underlying molecular defects and the actual management of bleeding episodes are not as well established as for hemophilia A and B. This article reviews these disorders, in terms of clinical manifestations and characterization of the molecular defects. The general principles of management are also discussed.

Blood Coagulation Disorders, Inherited↗