The history provides important clues to the etiology of bleeding. With few exceptions, the rare hereditary disorders produce deficiency or dysfunction of a single clotting factor, whereas the much more common acquired disorders cause multiple factor abnormalities. All congenital bleeding disorders are inherited in an autosomal fashion, except for the sex-linked recessive hemophilias and the very rare Wiskott-Aldrich syndrome. The most common inherited bleeding disorder is von Willebrand disease (vWD), an autosomal dominant condition that produces combined platelet-vessel wall dysfunction in up to 1% of the population. Fortunately, despite its prevalence, vWD is usually so mild that it remains undiagnosed. Although much less common, the hemophilias are the most likely genetic disorders to result in clinically significant bleeding. Deficiency of factor VIII (hemophilia A) may be up to ten times more common than the milder factor IX deficiency (hemophilia B). Unlike vWD, which affects men and women with equal frequency, the X-linked recessive inheritance pattern of the hemophilias dictates an almost exclusively male occurrence. (Some female carriers have factor levels as low as 50% and can exhibit mild increased bleeding tendencies.) All other inherited factor deficiencies are very rare autosomal recessive conditions; for these reasons, a thorough negative family history virtually excludes a diagnosis of hereditary coagulopathy. Furthermore, almost all inherited coagulation disorders manifest in childhood, making a new diagnosis in an adult a distinct rarity.

In taking the history, patient reports of “easy bleeding,” excessive bruising, or heavy menses are so common and nonspecific that they are all but useless. Detailed answers to the following questions should be sought: (a) Has there been excessive bleeding during or after surgery (especially oral surgery) or following significant trauma? (b) Has bleeding required transfusion or reoperation? The answers to these two questions can be very telling; an adult who has never experienced significant bleeding spontaneously or following surgery or trauma is extremely unlikely to have a hereditary disorder (at least one of clinical significance). If there is a suggestive history, the following questions help confirm the problem and point to the cause: (a) When did hemorrhage occur in relation to trauma or surgery? (Intraoperative bleeding suggests a platelet or vessel disorder, whereas delayed bleeding is more indicative of a soluble factor problem.) (b) What drugs have been taken? Particular attention should be paid to drugs affecting platelet numbers (e.g., immunosuppressive chemotherapy and alcohol) or function (e.g., aspirin, clopidogrel, glycoprotein IIb/IIIa inhibitors, and nonsteroidal anti-inflammatory agents) or those impairing synthesis of vitamin K-dependent clotting proteins (e.g., warfarin and antibiotics).

Petechiae (especially in dependent, high venous pressure areas), purpura, and persistent oozing from skin punctures or mucosal sites are most characteristic of platelet disorders. Palpable purpura is a sign of small artery occlusion usually associated with vasculitis of collagen-vascular disease (i.e., polyarteritis, systemic lupus erythematosus [SLE]), endocarditis, or severe sepsis. Larger vessel occlusions from disseminated intravascular coagulation (DIC) may cause the extensive ecchymoses of purpura fulminans. By contrast, factor deficiencies (especially the hemophilias) usually cause deep muscle and joint bleeding resulting in ecchymoses, hematomas, and the most characteristic feature, hemarthroses.

Basic screening tests of clotting function are indicated for patients undergoing surgery or invasive procedures and for those with a history that suggests a bleeding disorder. Clotting tests are also useful in patients undergoing massive transfusion, anticoagulation, or thrombolytic therapy. When indicated, a platelet count, PT, and aPTT usually suffice to exclude clinically important bleeding disorders. (Neither the PT nor aPTT will detect factor XIII deficiency, fortunately a rare cause of hemorrhage.) Not all prolongations of the PT and/or aPTT signify an increased risk of hemorrhage. For example, deficiencies of factor XII, high-molecularweight kininogen or prekallikrein or the presence of anticardiolipin antibody, also known as lupus anticoagulant, may prolong in vitro clotting tests without increasing bleeding risk. (In fact, anticardiolipin antibodies are more likely to result in clotting than bleeding.)

It has long been routine to measure PT, aPTT, and platelet count at the time of admission in almost all hospitalized patients. However, in the absence of a history suggesting hemophilia, vWD, or heparin use, measurement of the aPTT is extremely unlikely to yield a true positive abnormality and thus is wasteful of money and blood. Likewise, the common practice of measuring both the PT and aPTT in all patients receiving warfarin or heparin is also uneconomical; aPTT determinations are unnecessary during therapy with only warfarin, and PT measurements rarely add to the care of patients receiving only heparin. PT and aPTT ordering should be unlinked and tailored to the clinical situation.

In the ICU, isolated platelet production defects are uncommon; when inadequate production accounts for thrombocytopenia, anemia and leukopenia usually coexist (i.e., complete marrow failure). In such cases, platelets are small and bone marrow examination shows a decreased number of megakaryocytes. Marrow failure may result from alcohol or radiation; a deficiency of vitamin B₁₂ or folate; infection with hepatitis B, Epstein-Barr virus, parvovirus, or cytomegalovirus; cytotoxic chemotherapy; or marrow infiltration with tumor, fibrosis, or granuloma. Selective failure of platelet production may occur with the use of gold, sulfas, and thiazides.

Excessive platelet consumption is the most common cause of thrombocytopenia and may be due to immunologic or nonimmunologic mechanisms. Laboratory clues to excessive platelet consumption include disproportionate numbers of large (young) platelets on peripheral smear and an increased number of marrow megakaryocytes. Nonimmunologic platelet consumption occurs in DIC, severe sepsis, some malignancies, microangiopathic hemolysis, and following cardiopulmonary bypass and splenic sequestration. Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are other nonimmunologic cause of thrombocytopenia in which platelets aggregate with abnormally large von Willebrand factor (vWF) multimers that result from a deficiency in a vWFcleaving protease. The often profound thrombocytopenia is accompanied by elevated serum lactate dehydrogenase (LDH) levels and the presence of schistocytes on the peripheral smear representing mechanical erythrocyte destruction. Only microangiopathic hemolytic anemia and thrombocytopenia are required for the diagnosis, despite the description of a classic “pentad,” which also includes renal dysfunction, neurologic abnormalities, and low grade fever. Numerous conditions, including cancer, pregnancy, antiphospholipid antibody syndrome, and pneumococcal infection can be associated with “TTP-like” syndromes as can medications, such as cyclosporine, clopidogrel, and some chemotherapeutic agents. The absence of significant fever and normal aPTT and PT seen with TTP-HUS can sometimes help differentiate it from DIC, which also can exhibit schistocytes on the peripheral smear. Unfortunately, increased coagulation parameters are not universally present in DIC, making the distinction difficult at times. HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) of pregnancy represents another condition with hemolysis and thrombocytopenia that may be difficult to discriminate from TTP-HUS. Elevated liver enzymes may be
helpful in differentiating the two, but pregnancy itself is not distinguishing since it is also a risk factor for TTP. Since HELLP syndrome usually resolves within 72 h of delivery, continued worsening of thrombocytopenia beyond this time should prompt strong consideration of TTP-HUS.

Immune-mediated thrombocytopenia occurs via production of platelet antibodies with subsequent destruction. The antibodies can be idiopathic, or induced by drugs, infections (e.g., cytomegalovirus, human immunodeficiency virus, Epstein-Barr virus, parvovirus), or alloimmune following transfusion or transplantation. Many drugs have been implicated as causes of thrombocytopenia. An extensive current list can be found at http://moon.ouhsc.edu/jgeorge/DITP.html. Drug-induced destruction of platelets usually occurs via the formation of antiplatelet antibodies, which bind normal platelets in the presence of the sensitizing drug but a few drugs, such as procainamide, induce autoantibodies that react with platelets even in the absence of the drug. A third mechanism of drug-induced thrombocytopenia involves a direct interaction between drug and platelets resulting in immune destruction. Tirofiban, for example, interacts with the glycoprotein IIb/IIIa receptor on platelets, changing their shape and thereby facilitating antibody recognition. Heparin, one of the most common drugs associated with thrombocytopenia, similarly binds platelet factor 4 (PF4) forming an immune complex which is recognized and destroyed.

Drug-induced thrombocytopenia can be overlooked because its onset is often a week or more after beginning the medication and there are no distinguishing clinical features. Nonetheless, recognition is important because the problem may sometimes be reversed by simply discontinuing the offending agent. After drug discontinuation, platelet counts often rise substantially within 5 days but full recovery may take 3 to 4 weeks. Platelet transfusions and corticosteroids may help restore platelet counts rapidly once the inciting drug is removed.

In acute ITP, immunologic platelet destruction usually follows a childhood viral illness. Steroids are frequently helpful if thrombocytopenia persists more than several weeks. In adults, ITP usually presents as a chronic disease, with counts ranging from 20,000 to 80,000/mm³. The spleen is the major site of platelet destruction of the IgG coated platelets. Splenectomy is indicated in the 10% to 20% of patients who fail to respond to steroids, or immune globulin. Anemia in ITP is secondary to blood loss, not immune hemolysis. Interestingly, despite sometimes profound reductions in platelet count, life-threatening bleeding is rare.

Bleeding rarely occurs in patients with platelet dysfunction alone. As a first step, potentially offending medications should be discontinued. Unless sequestered or destroyed, transfused platelets quickly restore coagulation competency. Platelet transfusions will effectively correct dysfunction induced by aspirin, clopidogrel, or the cardiac bypass pump. Platelet transfusion is also transiently useful when the platelet environment is abnormal, as in uremia, paraproteinemia, or after treatment with high-dose penicillin or dextran. However, it is better to correct the underlying defect using dialysis, plasmapheresis, or by discontinuing the offending drug.

Treatment of chronic dialysis in patients who are bleeding requires a multifaceted approach, including adequate dialysis to remove uremic toxins. Functional defects caused by uremia and vWD may at least temporarily be corrected with fresh frozen plasma (FFP), arginine vasopressin also known as desmopressin (DDAVP), or cryoprecipitate. By releasing factor VIII/vWF multimers, DDAVP in doses of 0.3 μg/kg IV or 3 μg/kg intranasally correct clotting abnormalities in at least half of all patients within 1 h. Unfortunately, effectiveness is limited by tachyphylaxis, which occurs usually by the second dose. By increasing the levels of functional factor VIII, vWF, and fibrinogen, cryoprecipitate is also useful in uremic coagulopathy. For long-term therapy, estrogens may be helpful. Although their mechanism of action is not entirely understood, estradiol working through estrogen receptors can increase clotting within a day of starting therapy.