A 76-year-old man underwent radical prostatectomy after a prostate biopsy revealed adenocarcinoma. The surgery was uneventful, but the patient lost 1000 mL of blood. Twenty-four hours after surgery, the patient became hypotensive, and his hemoglobin concentration decreased from 14 to 6.2 g/dL. Exploratory surgery was performed, and large clots were found but no source of the bleeding. He was given 9 U of packed red blood cells in 24 hours, and his hemoglobin concentration increased to 9 g/dL. On physical examination, the patient had a blood pressure of 150/70 mm Hg, temperature of 38.2°C, and pulse rate of 104/min. He underwent intubation for respiratory support and was sedated. No ecchymosis, mucosal hemorrhage, or petechia was noted. His abdomen was mildly distended and firm with decreased bowel sounds. No hepatosplenomegaly was evident. Findings on lymphatic, cardiovascular, and respiratory examinations were normal. Laboratory tests showed a hemoglobin concentration of 10.1 g/dL, white blood cell count of 19.3 × 109, platelet count of 208 × 10g/L, creatinine level of 1.7 mg/dL, international normalized ratio of 1.1, and activated partial thromboplastin time9United States Pharmacopeial Convention, Inc. Hemophilia management.Transfus Med Rev. 1998; 12: 128-140Abstract Full Text PDF PubMed Scopus (8) Google Scholar of 50 seconds aPTTT. Sodium, potassium, alkaline phosphatase, aspartate aminotransferase, and bilirubin levels were within normal limits. 1.Which one of the following conditions is not associated with an isolated prolonged aPTT as seen in this patient? a.Hemophilia Ab.Hemophilia Bc.Lupus anticoagulantd.von Willebrand diseasee.Acute disseminated intravascular coagulation DIC Both hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) produce a prolonged aPTT due to deficiencies in coagulation factors found in the intrinsic coagulation pathway. Any patient who has an isolated prolonged aPTT with no obvious explanation (ie, heparin or warfarin use or liver disease) should be evaluated for the presence of either a deficiency or an inhibitor of a coagulation factor. In male patients, the presence of hemophilia should be excluded with appropriate testing. Up to 20% of cases of hemophilia occur in families with no prior history of hemophilia, reflecting spontaneous mutations in the respective factor VIII and IX genes. In some patients, hemophilia does not manifest until a stressful situation like surgery occurs. Lupus anticoagulants are antibodies (IgG and IgM) directed against phospholipids, crucial components of the aPTT assay system. Thus, the presence of lupus anticoagulants results in a prolongation of the aPTT. Lupus anticoagulants have been associated with thrombotic diathesis, spontaneous abortion, thrombocytopenia, neurologic disorders, and, less frequently, hemorrhage. Even though hemorrhagic diathesis is a rare phenomenon due to lupus anticoagulant, bleeding complications,1Ordi J Vilardel M Oristrcll J et al.Bleeding in patients with lupus anticoagulant [letter].Lancet. 1984; 2: 868-869Abstract PubMed Scopus (16) Google Scholar including epistaxis, hematemesis, joint bleeding, and spontaneous hematoma, have been reported with this condition. Based on our patient's clinical presentation and laboratory test results, a lupus anticoagulant is in the differential diagnosis. The most common congenital bleeding disorder is von Willebrand disease. This group of disorders is characterized by quantitative or qualitative defects in the von Willebrand factor (vWF), a protein that mediates platelet adhesion. The vWF has a separate function of binding to factor VIII coagulant activity (VIII:c) to protect against degradation. The aPTT is prolonged in von Willebrand disease when factor VIII :c is less than 25% because of decreased vWF to prevent the degradation of the factor VIII:c. In severe forms of von Willebrand disease, the bleeding manifestations can present as hemarthrosis, dissecting intramuscular hematomas, and serious hemorrhage due to traumatic injuries or after surgical procedures, as in our patient. Acute DIC is a syndrome characterized by excessive protease activity in the blood, resulting in formation of soluble fibrin and fibrinolysis. In the acute setting, accelerated, extrinsic coagulation components (factors VII, X, V, and prothrombin) are consumed, and a prolonged prothrombin time (PT) is observed more commonly than a prolonged aPTT. Acute DIC is the least likely condition in our patient. He had a normal PT, normal fibrinogen levels, and negative soluble fibrin monomers, factors that exclude the diagnosis of DIC. 2.Which one of the foliowing would be most useful in the initial assessment of this patient? a.History and physical examinationb.Bleeding timec.Platelet countd.Prothrombin timee.Activated partial thromboplastin time In most cases, a thorough history and physical examination will yield vital diagnostic information that may indicate an underlying bleeding disorder. The characteristics of the bleeding event in relationship to its sites and its timing often reveal the general type of coagulopathy involved. Patients with defects of primary hemostasis (eg, thrombocytopenia or abnormal platelet function) tend to have superficial hemorrhage into the skin or mucous membranes that occurs either spontaneously or immediately after trauma. Petechia, ecchymosis, purpura, gastrointestinal or genitourinary tract bleeding, hemoptysis, or epistaxis is a typical manifestation of defective primary hemostasis. In contrast, patients with abnormalities of secondary hemostasis (eg, coagulation factor deficiency) characteristically develop extensive deep tissue hemorrhage such as hemarthrosis, hematomas, or retroperitoneal bleeding, which may be delayed in onset up to 24 to 48 hours after surgery or trauma. Of note, although a family history of bleeding problems is helpful in elucidating the nature of a suspected coagulopathy, no family history does not exclude the possibility of a hereditary bleeding disorder. Our patient underwent a partial nephrectomy due to a motor vehicle accident in 1954, which required 25 U of blood transfusions. After working with cattle, he has had multiple lower extremity bruises. From 1978 until 1992, he had 5 episodes of gross hematuria with clots, and cystoscopy showed no bleeding source. His aPTT was recorded at 39 seconds during one of those episodes of hematuria in 1992, when the standard upper limit for aPTT was 37 seconds. He underwent transurethral prostatic resection because of benign prostatic hyperplasia and developed gross hematuria; 4 U of blood was necessary because his hemoglobin concentration decreased from 12 to 8 g/dL. His family history is notable for a brother who died at the age of 22 because of a brain hemorrhage. The patient's daughter had severe bleeding for 2 days after tonsillectomy. The bleeding time is fraught with potential technical artifact, and its results are susceptible to misinterpretations that must be recognized. The reproducibility of bleeding times is influenced by several variables, including the direction, size, and depth of the incision, as well as the skin temperature and vascularity at the wound site.2Bums FR Lawrence C Bleeding time: a guide to its diagnostic and clinical utility.Arch Pathol Lab Med. 1989; 113: 1219-1224PubMed Google Scholar No bleeding time was performed in our patient. A low platelet count could be the first sign of an underlying defect in primary hemostasis. However, factors such as improper blood sampling, platelet satellitism, ex vivo platelet clumping, and cold agglutinins can produce spuriously low platelet counts, a phenomenon known as pseudothrombocylopenia. Ethylenediaminetetraacctic acid-induced platelet clumping is probably the most common cause of pseudothrombocytopenia, with reported incidences ranging from 1 in 50 to 1 in 1000 hospitalized patients.3Janlunen E Inherited giant platelet disorders.Eur J Haematol. 1994; 53: 191-196Crossref PubMed Scopus (37) Google Scholar4Lombarts AJ dc Kieviel W Recognition and prevention of pseudothromhocytopenia and concomitant pseudoleukocytosis.Am J Clin Pathol. 1988; 89: 634-639PubMed Google Scholar Therefore, if a patient has a low platelet count, a peripheral blood smear should be examined and a repeated complete blood cell count in citrate should be performed to prevent platelet clumping produced by ethylenediaminetetraacetic acid. Our patient had normal platelet counts. Even though the PT and aPTT are used as screening tests to assess primary bleeding disorders, many factors can produce false-positive test results, eg, drugs (heparin and warfarin), liver disease, and rare deficiencies such as factor XII, prekallikrein, and high-molecular-weight kininogen with no bleeding complications. Our patient had normal liver function test results, and he was taking no drugs that would affect his coagulation system. 3.Which one of the following special coagulation tests would be least helpful in determining the diagnosis in this patient? a.Coagulation factor assaysb.Ristocetin cofactor activityc.vWF antigend.Dilute Russell viper venom time (dRVVT)e.Platelet aggregation studies Coagulation factor assays are necessary to diagnose and to distinguish between hemophilia A and hemophilia B. Clinically, hemophilia B is indistinguishable from hemophilia A. The recommended panel of tests to diagnose von Willebrand disease includes factor VIII activity; vWF antigen; vWF activity as determined by ristocetin cofactor, which measures the binding activity of vWF to platelet glycoprotein lb; bleeding time; and vWF multimer analysis, which helps to classify von Willebrand disease as type I (all proportionally decreased normal multimer distribution), type II (absent high and intermediate multimer), and type III (undetcctable multimer). Our patient's ristocetin cofactor and vWF antigen values were in the normal range. The prolongation of aPTT by a lupus anticoagulant is due to binding of lupus anticoagulant antibodies to phospholipids in the FP and partial aPTT reagents, resulting in interference with the assembly of the prothrombinase complex in vitro. The dRVVT is based on the ability of the snake venom, Russell viper venom, to activate factor × to Xa.5Brandt JT Triplett DA The effect of phospholipid on the detection of lupus anticoagulants by the dilute Russell viper venom time.Arch Palhol Lab Med. 1989; 113: 1376-1378PubMed Google Scholar Consequently, the dRVVT measures the rate of formation and activity of the prothrombinase complex in producing thrombin. The normal range for the dRVVT is 24 to 37 seconds. The dRVVT is prolonged in the presence of a lupus anticoagulant. In addition, on mixing with normal plasma, the dRVVT remains inhibited. Our patient had normal dRVVT test results. Platelet aggregation studies are used to diagnose hereditary disorders of platelet function such Bernard-Soulier syndrome, Glanzmann thrombasthenia, and storage pool disease. These disorders present with the clinical manifestations of defects in primary hemostasis: petechiae, bruising, and epistaxis. The aPTT is normal in these conditions. Our patient had no clinical manifestations of primary hemostasis defects. Coagulation factor assays in our patient were normal, except for the factor IX level of 23% (reference range, 65%-140%), confirming the diagnosis of hemophilia B. 4.Which one of the following treatment modalities would be the best choice in this patient? a.Fresh frozen plasmab.Cryoprecipitatec.Prothrombin complex concentratesd.High purified factor IX concentratese.Recombinant factor IX Plasma (fresh frozen plasma or cryoprecipitate) contains, by definition, 1 U of factor IX per milliliter. The main disadvantage of plasma is the inability to increase the factor IX level to greater than 10% to 15% of normal because of volume constraints. Since 1969, the use of prothrombin complex concentrates and subsequently high purified factor IX concentrates has been the standard treatment of hemophilia B. However, these products have been associated with viral transmission (hepatitis B and C and human immunodeficiency virus), DIC, and thromboembolism.6Roberts HR Fiberst ME Current management of hemophilia B.Hematol Oncol Clin North Am. 1993; 7: 1269-1280PubMed Google Scholar The best treatment of hemophilia B is recombinant factor IX (rFIX). In the early 1980s, investigators at Oxford and Seattle cloned the complementary DNA for factor IX.7White G Shapiro A Ragni M et al.Clinical evaluation of recombi-nant factor IX.Semin Hematol. 1998; 35: 33-38PubMed Google Scholar This led to the development of rFIX. Recombinant factor IX has been shown to decrease events of thromboembolism and DIC.7White G Shapiro A Ragni M et al.Clinical evaluation of recombi-nant factor IX.Semin Hematol. 1998; 35: 33-38PubMed Google Scholar The efficacy of rFIX has proved to be equal to other hemophilia products.7White G Shapiro A Ragni M et al.Clinical evaluation of recombi-nant factor IX.Semin Hematol. 1998; 35: 33-38PubMed Google Scholar Because of major surgery and the complication of retroperitoneal bleeding, our patient Was treated with rFIX, targeting the factor IX level at 100% for a total of 7 to 10 days. He had no further bleeding complications. 5.Which one of the following would be the least likely complication in this patient? a.Hemophiiic arthropathyb.Pseudotumorsc.Factor IX inhibitor antibodiesd.Hepatitise.Intracrania! hemorrhage Hemarthrosis is the most common manifestation of hemophilia B and hemophilia A. Repeated episodes of hemarthrosis result in chronic, crippling hemophilic arthropathy. In decreasing order of frequency, the most commonly involved joints are the knee, elbow, ankles, shoulder, wrist, and hip. Pseudotumors are masses of liquefied tissue and blood that begin as hematomas in the subperiosteal area of bone and soft tissue. Expansion may lead to compression or destruction of adjacent organs. The only reliable treatment is surgical removal of the entire mass; incomplete excision typically leads to a recurrence. In approximately 1 % to 4% of patients with hemophilia B, inhibitor antibodies develop that inactivate infused factor IX,8Barthel M Clinical efficacy of prothrombin complex concentrates and recombinant factor VIIa in the treatment of bleeding episodes in patients with factor VII and IX inhibitors.Thromb Res. 1999; 95: S31-S38Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar making treatment of subsequent bleeding episodes more difficult. Patients are classified as either low responders (administration of clotting9United States Pharmacopeial Convention, Inc. Hemophilia management.Transfus Med Rev. 1998; 12: 128-140Abstract Full Text PDF PubMed Scopus (8) Google Scholar factor results in little or no increase in inhibitor level) or high responders (substantial increase in inhibitor level after factor exposure). Patients who have low titers and are low responders can be managed with normal or greater doses of factor IX, more frequent infusions, or both. Patients with high titers who are high responders usually cannot be treated with increased doses of clotting factor, and alternative therapy is necessary. Approximately 90% of patients who received clotting factor before the availability of viral inactivation methods in the mid-1980s test positive for antibodies to hepatitis B and C In 15% to 20% of hemophilic patients infected with hepatitis C, the disease progresses to cirrhosis, end-stage liver disease, or hepatocellular carcinoma.10Lee CA Hepatitis C and haemophilia [editorial].BMJ. 1995; 310: 1619-1620Crossref PubMed Scopus (12) Google Scholar The introduction of rFIX has reduced the risk of hepatitis considerably. Clinical studies have shown that patients treated with rFIX do not have seroconversion for hepatitis A, B, and C.7White G Shapiro A Ragni M et al.Clinical evaluation of recombi-nant factor IX.Semin Hematol. 1998; 35: 33-38PubMed Google Scholar Because our patient has been treated with only rFIX, he is less likely to develop hepatitis as a complication of his hemophilia B therapy. Intracranial hemorrhage is one of the major causes of death in patients with hemophilia B and may occur even in the absence of recognizable trauma. Any sign or symptom suggestive of intracranial hemorrhage should be treated as a potential medical emergency. Hemophilia B (Christmas disease) is a hereditary hemorrhagic disorder characterized by genetic mutations leading to deficiency of factor IX coagulant activity. The incidence of hemophilia B is estimated at approximately 1 in 30,000 live male births.11McGraw RA Davis LM Lundblad RL Stafford DW Roberts HR Structure and function of factor IX: defects in haemophilia B.Clin Haematol. 1985; 14: 359-383PubMed Google Scholar It is inherited in an X-linked recessive pattern. The gene is located in the telomeric end of the long arm of the × chromosome at Xq26-27. Males are clinically affected, and female carriers are usually asymptomatic. Female carriers can be symptomatic, however, and have a factor IX level that is less than 20% of normal in extreme lyonization or abnormalities of the × chromosome. In one third of all persons, hemophilia B arises by de novo mutations in the factor IX gene. The clinical presentation of hemophilia B is indistinguishable from hemophilia A because factor VIII combines with factor IX, calcium, and phospholipid to convert factor × to Xa. Therefore, a deficiency in factor VIII (hemophilia A) or factor IX (hemophilia B) produces the same deficits in the intrinsic coagulation pathway, resulting in the same clinical presentation. Depending on the factor IX levels, hemophilia B is classified as severe (<1 %), moderate (1 %-5%), or mild (6%-25%). The severity of hemophilia B correlates with the risk of bleeding complications. The clinical manifestations of hemophilia B include hemarthrosis, pseudotumors, neurologic symptoms (intracranial hemorrhage, peripheral nerve compression by hematoma), soft tissue hemorrhage, and hematuria. Hemophilia B must be distinguished from hemophilia A with use of the coagulation factor assay. Acquired deficiency of factor IX commonly occurs in hepatic disease, vitamin K deficiency, and after administration of warfarin therapy. Disease states that may be associated with acquired factor IX deficiency include amyloidosis, nephrotic syndrome, and Gaucher disease. In amyloidosis, factor IX and factor × are believed to bind to the amyloid fibrils in the spleen and liver, resulting in deficiency.12McPhcrson RA Onstad JW Ugorctz RJ Wolf PL Coagulopathy in amyloidosis: combined deficiency of factors IX and X.Am J Hematol. 1977; 3: 225-235Crossref PubMed Scopus (59) Google Scholar Persons with nephrotic syndrome lose factor IX protein in the urine. In Gaucher disease, the plasma half-life is shortened, presumably because of binding and clearance of the protein by cerebroside deposits. Replacement therapy is dictated by the severity of the disease and the presence of bleeding. In minor hemorrhage (superficial hematoma), the recommended factor IX activity is 20% to 30%, and duration of treatment is 1 to 2 days. In moderate hemorrhage (hematuria), the factor IX activity is 25% to 50%, and duration of treatment is 3 to 7 days. The recommendation for major hemorrhage (surgery, dental extraction) is a factor IX level of 50% to 100%, and duration of treatment is 7 to 10 days. The usual loading dose is 40 to 60 U and then a maintenance dose of 10 to 12 U. Replacement therapy should also be judiciously and cautiously given because of the cost of the available factor IX products. One vial of factor IX (1000 U) is $983. The finding of an isolated aPTT requires prompt evaluation of the underlying cause. A history of bleeding forms the basis of the diagnosis and treatment of hemonhagic disorders. Since many of these disorders are inherited, the family history is crucial. A constellation of hemorrhagic symptoms, rather than any single symptom, is most helpful in suggesting the cause of the disorder. Thus, spontaneous hemarthrosis and muscle hemorrhages are highly suggestive of severe hemophilia, whereas epislaxis, gingival bleeding, and menorrhagia are more commonly found in patients with thrombocytopenia, platelet disorders, or von Willebrand disease. After a thorough bleeding history is obtained, the next step is to proceed with a coagulation work-up, with mixing studies with clotting factor assay as indicated (if aPTT corrects), or work-up for lupus anticoagulant or factor inhibitor (if aPTT remains inhibited on the mixing study). Hemophilia should be considered in the differential diagnosis.
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