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Two patients with severe bleeding complications under oral anticoagulant treatment are presented, in one case caused by pharmacokinetic drug interference (phenylbutazone), in the other by genetic predisposition to bleeding induced by coumarin anticoagulants. Another patient with decreasing INR due to drug interference (rifampicin) is presented as well. The possibility of drug interferences with coumarin anticoagulants has to be anticipated, whenever the medication of an orally anticoagulated patient is changed. A founder mutation of the factor IX propeptide constitutes a genetic predisposition to bleeding in patients put on coumarins. Its presence should be excluded in any patient suffering from hemorrhagic complications after starting anticoagulation when INR values are in the target range.

Two sisters having suffered from deep vein thrombosis while taking oral contraceptives are presented. Investigation for thrombophilia in 1993 was unrevealing. After the discovery of activated protein C (APC) resistance caused by the factor V R506Q (FV Leiden) mutation in 1993/1994, reinvestigation showed homozygous FV Leiden mutation in both sisters. APC resistance is the most frequent hereditary thrombophilia known so far. Diagnosis, prevalence and clinical significance of this thrombophilic defect are shortly discussed.

Congenital afibrinogenemia is a rare autosomal recessive hemostatic disorder leading to unclottable global coagulation tests. Furthermore, it is associated with abnormal platelet aggregation and with severe bleeding episodes if untreated. Surprisingly, thrombotic complications may be observed quite frequently in afibrinogenemic patients following replacement of fibrinogen. A case of congenital afibrinogenemia is described in a patient who suffered from severe bleeding episodes in the absence of replacement therapy but developed a deep vein thrombosis with multiple pulmonary emboli after fibrinogen replacement and surgical treatment of a hip fracture, despite conventional heparin prophylaxis.

We describe a 56-year-old patient with multiple myeloma and very high paraprotein concentration (IgG kappa). Coagulation studies showed unclottable thrombin and reptilase times caused by impaired fibrin polymerization presumably due to the paraproteinemia. There was no obvious bleeding tendency. The differential diagnosis of thrombin time prolongation includes inhibition of the added thrombin by exogenous heparin, hirudin or seldom by endogenous heparin-like anticoagulants or by acquired (bovine) thrombin antibodies, qualitative fibrinogen disorders (congenital and acquired dysfibrinogenemia), quantitative fibrinogen disorders (severe hypo- and afibrinogenemia) and delayed fibrin polymerization due to fibrin/fibrinogen degradation products, paraproteins and antibodies against fibrin(ogen). In multiple myeloma, thrombin time prolongation may seldom be due to endogenous heparin-like anticoagulants or antibodies to thrombin and more frequently to impaired fibrin polymerization by paraproteins. Simultaneous reptilase time prolongation as present in this case hints to this latter possibility.

A 68-year-old woman suffered from spontaneous hemarthrosis of the right elbow joint in april 1994. Cutaneous ekchymoses had been noted since summer 1993. Prothrombin time was prolonged (Quick percentage 40-50%) and was not corrected by prolonged administration of vitamin K. Coagulation studies showed isolated factor X (FX) deficiency without circulating FX inhibitor. This suggested the diagnosis of systemic amyloidosis which was retrospectively confirmed in small bowel biopsy specimens obtained one year before. Bilateral femoral head necrosis and femoral neck fracture due to amyloidosis, necessitated orthopedic surgery. The patient died four weeks postoperatively after several episodes of bleeding complications. Isolated FX deficiency may be hereditary but should--in the clinical context--also evoke the diagnosis of systemic amyloidosis. The possible bleeding tendency associated with amyloidosis is not attributable to acquired FX deficiency alone, but may also be caused by amyloid deposition in the microvasculature leading to acquired vascular hemorrhagic diathesis.

We report the history of a 77-year-old man with Osler-Weber-Rendu disease (hereditary hemorrhagic telangiectasia) who suffered from recurrent epistaxis and chronic bleeding anemia for many years. Hereditary hemorrhagic telangiectasia is a rare congenital disease, that is characterized by telangiectases of the nasal and oral mucosa, the gastrointestinal tract and the skin. Arteriovenous malformations of the lung and the brain may be present. The genetic and pathologic features, the clinical manifestations and the differential diagnosis are shortly presented. The management is not validated by controlled studies and is mainly based on clinical experience. It involves supportive therapy with iron supplementation and erythrocyte transfusions, if needed, for chronic bleeding anemia, aminocaproic acid, tranexamic acid or oestrogen-progesterone therapy to prevent mucosal bleeding, cauterisation, photocoagulation, transcatheter embolotherapy or surgery to treat the vascular abnormalities.

By virtue of a severely prolonged aPTT with a normal thromboplastin time (prothrombin time) and a normal thrombin time, severe FXII deficiency has been diagnosed in a woman without a bleeding diathesis or a history of thromboembolic complications. A deficiency of a factor of the contact activation system (FXII, prekallikrein, high molecular weight kininogen) is usually diagnosed during routine coagulation tests demonstrating a prolonged aPTT. The severe and partial deficiency of FXII, of prekallikrein or high molecular weight kininogen is not associated with a bleeding tendency. In contrast, severely factor XI deficient subjects may suffer from a mild hemorrhagic diathesis, whereas FVIII deficiency (hemophilia A, autoimmune "hemophilia", von Willebrand disease) and FIX deficiency (hemophilia B) are associated with a bleeding tendency of varying severity, depending on the clotting activity of FVIII or FIX, respectively. An isolated prolongation of the aPTT due to a lupus anticoagulant, however, is frequently associated with arterial and/or venous thrombosis. Therefore, in case of a prolongation of the aPTT, its cause has to be determined.

A 76-year-old man under long term oral anticoagulant treatment showed unclottable prothrombin time (PT) without overt bleeding. After oral administration of vitamin K1, PT remained severely prolonged and the patient was hospitalized. INR was 8.0 and responded to parenteral vitamin K. Cholestasis resulting in poor intestinal vitamin K resorption was assumed to have caused "overanticoagulation". Quick test is a global clotting test for the extrinsic and common pathways of the coagulation system. Increased PT, i.e. decreased Quick percentage, may be due to different conditions and should--if unexplained--be further analyzed by assaying factors II, V, VII, X and fibrinogen. Preanalytical problems, plasma dilution with clotting factor-free volume replacement, decreased vitamin K-dependent clotting factors (oral anticoagulation, intoxication with certain rodenticides, vitamin K deficiency), impaired liver synthetic capacity, disseminated intravascular coagulation, or massive heparin contamination may cause prolonged PT. Newborns physiologically have longer PT and should receive vitamin K prophylaxis.

Hemorrhagic complications in CLL are most often related to thrombocytopenia either due to decreased megakaryopoiesis caused by diffuse lymphocytic bone marrow infiltration or to increased peripheral platelet consumption by platelet autoantibodies (immune thrombocytopenia), both being typical manifestations of the disease. Disseminated intravascular coagulation (DIC) does not belong to the spectrum of CLL-related complications. In the case here reported with DIC and newly diagnosed CLL the leukoerythroblastic blood changes hinted to bone marrow infiltration by another neoplastic process in addition to CLL. Bone marrow biopsy revealed infiltration by metastatic carcinoma of the prostate in addition to that by CLL, the former being responsible for triggering severe DIC leading to fatal intracranial bleeding.

A 46-year old nurse complaining of multiple hematomas including bleeding into the tongue was referred for hemostasis evaluation. A very low Quick percentage value, i.e. a severely prolonged prothrombin time with severely depressed vitamin K-dependent coagulation factors (FII:C, FVII:C, FX:C) and normal FV:C and fibrinogen level was found. In the absence of cholestasis, malabsorption and broad-spectrum antibiotic therapy, ingestion of vitamin K antagonists was suspected. Three years previously, she had been on oral anticoagulant treatment with phenprocoumon (Marcoumar) for postoperative pulmonary embolism. She denied having voluntarily ingested anticoagulant drugs. A high plasma level of coumarins was found. To exclude accidental ingestion, the patient's son living in the same household was tested as well. Surprisingly, a low level of coumarin was found also in his plasma. We suspect that the patient voluntarily intoxicated herself and gave a low dose of coumarin anticoagulant to her son as well.

Based on the description of a severe bleeding disorder in a young child a short overview on the genetics, the epidemiology, the pathophysiology, the clinical manifestations and the laboratory diagnosis of factor XIII deficiency is presented. The impressive clinical signs with bleeding starting in the neonatal period (prolonged bleeding from the umbilical cord), followed by severe, life-threatening episodes of intracranial hemorrhages should raise the clinical suspicion of FXIII deficiency. Difficulty of laboratory diagnosis is stressed. The importance of repeating initially negative screening tests and of performing a quantitative FXIII assay in the presence of strong clinical suspicion is strengthened. The diagnosis of factor XIII deficiency is difficult but has important therapeutic consequences: patients with documented severe deficiency should be put on regular substitution with factor XIII concentrates. Appropriately timed periodic infusions of such factor XIII concentrates enable patients to live normal lives, free from catastrophic bleeding episodes.

Venography is still the gold standard for objective diagnosis of deep venous thrombosis (DVT). However, this investigation is costly and time-consuming, demands technical expertise and has potential side-effects. To reduce the number of phlebographies a simple, rapid and reliable screening test for exclusion of DVT would be greatly appreciated. In many studies markers of activated coagulation and fibrinolysis such as thrombin-antithrombin complex (TAT), prothrombin fragment 1 + 2 (F 1 + 2) and D-dimers, respectively, were investigated with respect to their potential use as screening tests. Especially D-dimers as assessed by ELISA have turned out to have high sensitivity and negative predictive value for DVT and could therefore serve as screening test for exclusion of DVT. However, most of the easier, more rapid D-dimer Latex tests which would be better suited for emergency situations as well as the TAT- and F 1 + 2-ELISA tests are according to most studies not sufficiently sensitive. In the present article the significance of the different activation markers in the diagnostic approach of DVT is discussed based on the literature.

Venous thromboembolic diseases are of major importance with respect to morbidity and mortality. Therefore, efficient prophylaxis is essential. Indication for thromboprophylaxis has to be made individually: In high risk situations, especially in orthopedic surgery, every patient should receive medical prophylaxis, e.g. with heparin, in addition to other preventive measures such as the wearing of elastic stockings or physiotherapy until full mobilization. For high-risk patients having a history of recurrent venous thromboembolism or which are suffering from a thrombogenic disease (e.g. myeloproliferative disorder, especially polycythemia vera, paroxysmal nocturnal hemoglobinuria, systemic lupus erythematosus, homocystinuria) or a hereditary thrombophilia (e.g. deficiency of antithrombin III, protein S, protein C or APC resistance), prophylactic measures should be more generally applied. In these patients, risk factors (e.g. oral contraceptive medication) or risk situations (e.g. long-distance travelling by car or airplane) have to be avoided whenever possible. In inevitable risk situations (e.g. perioperative or peripartal period) prophylaxis is mandatory. It is generally limited to the period of elevated thrombogenic risk and is often effected by application of a low molecular weight heparin. Patients with a history of recurrent thromboembolic events despite elimination of all avoidable risk factors should get a lifelong prophylaxis, usually with oral anticoagulants.

The overall incidence per year of deep vein thrombosis is about one per thousand, but may be much higher in the presence of certain clinical risk factors such as advanced age, immobilization, surgical procedures, pregnancy, puerperium, use of oral contraceptive agents and malignancy. Moreover, homocystinuria, nephrotic syndrome, systemic lupus erythematosus and hematological disorders such as paroxysmal nocturnal hemoglobinuria or myeloproliferative syndromes predispose to thrombotic disease. Evaluation of the patient with thromboembolism should include detailed history, clinical examination and laboratory investigation to exclude these secondary thrombophilic states. Primary or hereditary thrombophilia is suspected mainly in patients suffering from (venous) thromboembolism at an early age (< 45 years), especially if recurrent and/or familial thrombosis is present. Hereditary thrombophilia may be due to deficiency of antithrombin III, protein C, protein S or plasminogen, some other defects being less well-established prethrombotic risk factors. These currently recognized primary prethrombotic molecular defects are found in 10 to 30% of patients with idiopathic thromboembolism. In the majority of cases the cause of thrombosis remains unknown.

Numerous patients with a thromboembolic history are referred to our Central Haematology Laboratory for a complete investigation of thrombophilia. Among them, patients with idiopathic thromboembolism represent the largest group. In collaboration with the obstetrician we control pregnant women at increased risk for thromboembolic complications. Individuals with myeloproliferative disorders often suffer from thromboembolism and are investigated at our Laboratory as well. Thirteen illustrative cases are presented, which are of diagnostic and/or therapeutic interest for the practitioner.