HEMOPHILIA AND RELATED CONDITIONS
• The hemophilias and von Willebrand disease (vWD) account for 80% to 85% of inherited bleeding disorders. Hemophilia A and B are X-linked, whereas vWD and rare bleeding disorders (RBDs) are autosomal disorders.
• The diagnosis of hemophilia and other inherited bleeding disorders should be confirmed by specific laboratory assays, because screening tests such as prothrombin time (PT) and activated partial thromboplastin time (aPTT) may be normal. Plasma levels of deficient factor determine clinical severity and management.
• Major complications associated with hemophilia are inhibitor development, hemarthrosis, and intracranial hemorrhage. Hemarthrosis is the most common and debilitating complication, and central nervous system bleeding is the most common cause of mortality in hemophilia. Mucosal bleeding and menorrhagia are the most common manifestations of vWD. Bleeding manifestations of RBDs are mild, although homozygotes can present with severe disease.
• Newborns have normal levels of factor VIII; therefore, the diagnosis of hemophilia A can be established at birth. Vacuum delivery should be avoided to prevent head bleeds.
• Women and adolescents with menorrhagia and no underlying pathology should be investigated for a bleeding disorder.
• Early and effective treatment and prophylaxis can prevent repeated hemarthrosis and joint destruction in persons with hemophilia. Patients should be tested annually for the presence of inhibitors.
• Wherever available and indicated, recombinant factor concentrates are preferred over plasma-derived products due to potential risk of pathogen transmission. Cryoprecipitate is not recommended. For mild and moderate hemophilia A and von Willebrand disease, the use of desmopressin (DDAVP) coupled with antifibrinolytics can obviate the use of concentrates. Continued vigilance should be implemented for new and emerging bloodborne pathogens.
• All patients with inherited bleeding disorders should be immunized against hepatitis A and B and followed in close collaboration with the local hemophilia treatment center (http://www2a.cdc.gov/ncbddd/htcweb/index.asp). The National Hemophilia Foundation’s (www.hemophilia.org) Medical and Scientific Advisory Committee (MASAC) guidelines for updated recommendations and product choice should be followed.
Hemophilia A and Hemophilia B
Hemophilia is an X-linked congenital bleeding disorder caused by a deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B). Hemophilia A is the most common severe bleeding disorder and affects 1 in 5000 males in the United States; hemophilia B occurs in 1 in 30,000 males.
The factor VIII gene is one of the largest genes and spans 186 kb of genomic DNA at Xq28. Inversion mutations account for 40% of severe hemophilia A, and deletions, point mutations, and insertions account for the remainder.
Hepatic and reticuloendothelial cells are presumed sites of factor VIII synthesis. Factor VIII is synthesized as a single chain polypeptide with three A domains (A1, A2, and A3), a large central B domain, and two C domains (Figure 1). The binding sites for von Willebrand’s factor (vWF), thrombin, and factor Xa are on the C2 domain, and factor IXa binding sites are on the A2 and A3 domains. The B domain can be deleted without any consequences. vWF protects factor VIII from proteolytic degradation in the plasma and concentrates it at the site of injury.
FIGURE 1 Factor VIII protein structure.
The factor IX gene is 34kb long and located at Xq26. It is a vitamin K–dependent serine protease composed of 415 amino acids. It is synthesized in the liver and its plasma concentration is about 50 times that of factor VIII. Gene deletions and point mutations result in hemophilia B.
Role of Factors VIII and IX in Coagulation
Factor VIII circulates bound to vWF. It is a cofactor for factor IX and is essential for factor X activation. In the classic coagulation cascade, activation of the intrinsic or extrinsic pathway of coagulation results in sufficient thrombin generation. However, this does not explain bleeding in hemophilia, because the extrinsic pathway is intact. This led to the revised cell-based model of coagulation.
The revised pathway incorporates all coagulation factors into a single pathway initiated by FVII and tissue factor. The contact factors (XI, XII, kallikrein, and high-molecular-weight kininogen) are not essential but serve as a backup. Following injury, encrypted tissue factor is exposed and forms a complex with factor VIIa. The tissue factor–factor VIIa complex activates factor IX to IXa (which moves to the platelet surface) and factor X to Xa. This generates small amounts of thrombin that activates platelets, converts platelet factor V to Va and factor XI to XIa, and releases factor VIII from vWF and activates it. The factor XIa activates plasma factor IX to IXa on the platelet surface, which together with factor VIIIa forms the tenase complex (factor VIIIa/IXa) that converts large amounts of factor X to Xa. Factor Xa forms a prothrombinase complex with FVa and converts large amounts of prothrombin to thrombin, called thrombin burst. This results in the conversion of sufficient fibrinogen to fibrin to form a stable clot. (Animations are available at the Foundation of Women and Girls with Blood Disorders (www.fwgbd.org and www.reddymed.com).
In hemophilia, lack of factor VIII or IX produces a profound abnormality. Factor Xa generated by FVIIa and tissue factor is insufficient because it is soon inhibited by tissue factor pathway inhibitor (negative feedback), and factors VIII and IX, which are required for amplifying the production of Xa, are absent. The primary platelet plug formation and initiation phases of coagulation are normal. Any clot that is formed (from the initiation phase) is friable and porous.
The diagnosis of hemophilia is often made following a bleeding episode or because of a family history; 30% of cases, however, have no family history. Based on the plasma levels of factor VIII or IX (normal levels are 50%–150%) that correlate with severity and predict bleeding risk, hemophilia is classified as mild (>5%), moderate (1%–5%) and severe (<1%) (Table 1). Approximately 65% of persons with hemophilia have severe disease, 15% have moderate disease, and 20% have mild disease. Most severe disease manifests by 4 years of age; moderate or mild disease is diagnosed later and often following bleeding secondary to trauma or surgery.
Hemophilia Severity and Clinical Manifestations
Hemophilia can be diagnosed in the first trimester, using chorionic villus sampling and gene analysis. In the second trimester, fetal blood sampling can be performed. Prenatal diagnosis to determine fetal gender can aid in the management of pregnancy and delivery.
The hallmark of severe hemophilia is hemarthrosis, or bleeding into the joint, that can occur spontaneously or with minimal trauma.
Although the immediate effects of a joint bleed are excruciating pain, swelling, warmth, and muscle spasm, the long-term effects of recurrent hemarthrosis include hemophilic arthropathy, which is characterized by synovial thickening, chronic inflammation, and repeated hemorrhages resulting in a target joint. Knees, elbows, ankles, hips, and shoulders are commonly affected. Disuse atrophy of surrounding muscles leads to further joint instability. Limitation of joint range of motion due to hemarthrosis often correlates positively with older age, nonwhite race, and increased body mass index, and it affects quality of life.
Muscle hematomas, another characteristic site of bleeding, can lead to compartment syndrome, with eventual fibrosis and peripheral nerve damage. Iliopsoas bleeds manifest with pain and flexion deformity. Gastrointestinal bleeding and hematuria occur less often.
Central nervous system (CNS) hemorrhage is a rare but serious complication with a 10% recurrence rate and is the leading cause of mortality in hemophiliacs. Although most newborns with severe hemophilia experience an uneventful course following vaginal delivery, vacuum extraction is associated with an increased CNS bleeding risk. The incidence of intracranial hemorrhage in newborns with hemophilia is 1% to 4%.
Hemophilia A and B are clinically indistinguishable, and specific factor assays are the only way to differentiate and confirm the diagnosis. Both should be differentiated from von Willebrand disease (vWD). The prothrombin time (PT), platelet function analyzer (PFA- 100), and fibrinogen are normal. (PFA, a platelet-function screening test, is replacing bleeding time, because the bleeding time has low sensitivity and specificity and is operator dependent.) The activated partial thromboplastin time (aPTT) is prolonged when the factor
levels are below 30%. Table 2 shows the characteristics and differences between the hemophilias and vWD. Female carriers may be asymptomatic except for those with extreme lyonization resulting in low factor VIII or IX levels. However some carriers may experience bleeding episodes even with levels of FVIII or IX in the 40% range.
Factor VIII levels increase throughout pregnancy and drop to prepregnancy levels following delivery, but factor IX levels remain constant throughout pregnancy.
Hemophilias and von Willebrand Disease: Key Characteristics and Differences
Abbreviations: APCC = activated prothrombin complex concentrates; aPTT = activated partial thromboplastin time; DDAVP = desmopressin; PFA = platelet function analyzer; PT = prothrombin time; RCo = ristocetin cofactor; VWF = von Willebrand factor; VWF:Ag = von Willebrand factor antigen.
The treatment for hemophilia consists of replacement therapy with intravenous factor VIII or factor IX concentrates produced by purification of donor plasma (plasma derived) (e.g., factor VIII: Hemofil M, Monoclate-P; factor IX: AlphaNine, Mononine) or in cell culture bioreactors (recombinant) (e.g., factor VIII: Afstyla, Helixate; factor IX: BeneFix, Rixubis). Careful screening of donors combined with heat treatment and viral inactivation methods have made plasma-derived products safer. Plasma-derived and recombinant products appear to have equivalent clinical efficacy. Recombinant factor concentrates are recommended, but if they are not available, plasma-derived concentrates can be used. Cryoprecipitate is no longer recommended because of concerns regarding pathogen safety.
Treatment administered only during bleeding symptoms is known as episodic therapy, and periodic administration of factor concentrates to prevent bleeding is known as prophylactic therapy. Response to treatment is more effective when it is administered early. Although prophylaxis prevents the development of joint disease, the high cost of factor replacement coupled with the need for venous access makes it expensive and difficult and out of reach for patients in the developing world.
The goal of treatment is to raise factor levels to approximately 30% or more for minor bleeds (hematomas or joint bleeds) and 100% for major bleeds (CNS or surgery). Giving 1 U/kg of factor concentrate raises plasma factor VIII levels by 2% and factor IX levels by 1.5% (except with the recombinant factor IX product, where it increases by 0.8%). The half-life of factor VIII is approximately 8 to 12 hours and that of factor IX is up to 24 hours. Factor concentrates can also be given by continuous infusion (3–4 U/kg/hour). The bolus dose varies from 25 to 50 U/kg depending on the severity, site, and type of bleeding and is dosed to the available vial size because of the cost of the products. Table 3 lists the dosing schedule for various types of bleeds.
Treatment of Bleeding Episodes and Desired Plasma Levels in Hemophilias A and B
Abbreviation: PT = physical therapy.
For short-term therapy (before dental procedures and minor bleeding episodes) in mild hemophilia A and vWD, the synthetic vasopressin analogue desmopressin acetate (DDAVP [Stimate]) is useful. It increases plasma concentrations of coagulation factor VIII and vWF three- to fivefold by releasing the endothelial stores. A DDAVP trial to determine response is helpful in selecting patients who might benefit from such therapy. For hemostatic purposes, intravenous (0.3 µg/kg in 50 mL of normal saline infused over 15–30 min) or intranasal dose (150 µg) can be used. The intranasal dose is 15 times larger than that recommended for diabetes insipidus. A multidose intranasal spray formulation (Stimate nasal spray) delivers 150 µg per spray. The recommended dosage is one spray for patients who weigh less than 50 kg and two sprays (one in each nostril) for those who weigh more than 50 kg. Desmopressin is ineffective in hemophilia B. Aspirin and aspirin-containing compounds should be avoided in persons with bleeding disorders because they interfere with platelet function and can exacerbate bleeding.
Antifibrinolytics such as ɛ-aminocaproic acid (Amicar) and tranexamic acid (Cyklokapron or Lysteda) are used as adjunct therapies and in mild hemophilia and can decrease the need for factor concentrates. The recommended dosage for ɛ-aminocaproic acid is 75 to 100 mg/kg/dose IV or orally every 4 to 6 hours (maximum 30 g/24 hours). The recommended dosage for tranexamic acid is 10mg/kg/dose IV or 25 mg/kg body weight orally, three times daily.
For prophylaxis, factor VIII 25 to 40 U/kg administered every other day or factor IX 25 to 40 U/kg twice weekly (because of the longer half-life of factor IX) is aimed at preventing joint disease. Prophylaxis may begin at 1 to 2 years of age and is continued lifelong. Self- infusion before any planned strenuous activity is recommended.
Because of the complications of central venous catheters (infections, thrombosis, and mechanical), use of a peripheral vein is encouraged. Over the last 2 years various modified factor products with prolonged half lives have been developed with an aim to decrease the frequency of infusions and improve quality of life for patients with hemophilia. These include PEGylation, fusion proteins with fusion of the factor protein to the Fc fragment of an immunoglobulin or albumin. In March 2014, the US FDA approved the first long acting Factor IX Fc fusion protein (Alprolix) for use in patients with hemophilia B after safety and efficacy was established in initial clinical trials in adult patients with hemophilia B. More recently in June 2014, rFVIII Fc fusion (Eloctate) was approved by the FDA for the treatment and prophylaxis of bleeding episodes in hemophilia A. Clinical trials are still ongoing with other prolonged half life factor concentrates.
Complications of Treatment
One of the most serious complications of hemophilia treatment is the development of inhibitors or neutralizing antibodies (immunoglobulin [Ig]G) that inhibit the function of substituted factor VIII and factor IX. Approximately 5% to 10% of all hemophiliacs and up to 30% of patients with severe hemophilia A develop inhibitors.
The incidence of inhibitors in hemophilia B is lower (1%–3%). Most factor VIII inhibitors arise after a median exposure of 9 to 12 days in patients with severe hemophilia A. They can be transient or permanent and should be suspected if a patient fails to respond to an appropriate dose of clotting factor concentrate. Inhibitors can exacerbate bleeding episodes and hemophilic arthropathy.
Inhibitor levels, measured using Bethesda units (BU), are classified as high titer (>5 BU) or low titer (<5 BU). In patients with low titer inhibitors, higher than normal doses of factor VIII or IX may be used to treat bleeding. For those with high-titer inhibitors, agents that bypass factor VIII or factor IX are used. These include recombinant activated factor VII and, in the case of hemophilia A, activated prothrombin complex concentrates (APCC) or recombinant porcine factor VIII (currently in prelicensure clinical trials). Immune tolerance induction, a long-term approach designed to eradicate inhibitors, is effective in 70% to 85% of patients with severe hemophilia A; the most important predictor of success of immune tolerance induction is an inhibitor titer of less than 10 BU at the start of immune tolerance induction.
Although inhibitors are rare in hemophilia B, they can result in anaphylaxis with exposure to factor IX–containing products. Immune tolerance regimens are associated with nephrotic syndrome and are successful in eradicating the inhibitor only in 40% of cases.
Another important complication of treatment is the transmission of bloodborne pathogens such as hepatitis B and C viruses and HIV. In the 1970s, lyophilized plasma factor concentrates of low purity resulted in the transmission of HIV, causing the deaths of many hemophiliacs. Currently, donor screening for pathogens coupled with viral attenuation by heat or solvent detergent technology make these products pathogen safe. However, nonenveloped virus (parvovirus and hepatitis A) and prions can resist inactivation and can be potentially transmitted.
Patients with bleeding disorders should be encouraged to attend the comprehensive hemophilia treatment centers, where they are educated, trained to self-infuse and calculate dosage, maintain treatment logs, and call for serious bleeding episodes. The mortality rate among patients who receive care at hemophilia treatment centers (HTCs) is lower than among those who do not: 28.1% versus 38.3%, respectively. At the HTCs, Hemovigilance for blood borne and emerging pathogens was maintained through participation in the Centers for Disease Control and Prevention’s (CDC) Universal Data Collection (UDC) project. The grant cycle of the UDC was completed in 2012, and a new surveillance instrument is currently in use that incorporates collecting information on co-morbidities and complications of bleeding disorders in this population.
Routine vaccination against hepatitis A and B is recommended.
Gene therapy offers promise of a cure but has not yet become reality. Two gene-therapy trials for hemophilia B had shown subtherapeutic or transient expression of factor IX. In December 2011, Nathwani and colleagues reported that a single injection of FIX expressing adenovirus-associated virus (AAV) vector was effective in treating patients with hemophilia B for more than a year. This has been a significant breakthrough in the treatment of hemophilia.
von Willebrand Disease
von Willebrand disease (vWD) is an inherited (autosomal dominant) bleeding disorder caused by deficiency or dysfunction of von Willebrand factor (vWF), a plasma protein that mediates platelet adhesion at the site of vascular injury and prevents degradation of factor VIII. A defect in vWF results in bleeding by impairing platelet adhesion or by decreasing factor VIII.
vWF is synthesized in endothelial cells and undergoes dimerization and multimerization, forming low-, intermediate-, and high- molecular-weight (HMW) multimers. The HMW multimers are most effective in promoting platelet aggregation and adhesion. Circulating HMW multimers are cleaved by the protease ADAMTS13, which is deficient in patients with thrombotic thrombocytopenic purpura.
vWD is the most common bleeding disorder, affecting 1% or more of the population. It occurs worldwide and affects all races. vWD is classified into three major categories: partial quantitative deficiency (type 1), qualitative deficiency (type 2), and total deficiency (type 3). There are several different variants of type 2 vWD: 2A, 2B, 2N, and 2M based on the phenotype. About 75% of patients have type 1 vWD.
Mucous membrane–type bleeding (e.g., menorrhagia, epistaxis) and excessive bruising are characteristic clinical features in vWD. Bleeding manifestations vary considerably, and in some cases, the diagnosis is not suspected until excessive bleeding occurs with a surgical procedure or trauma. Although excessive menstrual bleeding may be the initial manifestation, it takes 16 years for a diagnosis of bleeding disorder. It is for this reason that the American College of Obstetrics and Gynecology recommended screening for hemostatic disorders in all adolescents and women presenting with menorrhagia and no pathology and before hysterectomy for menorrhagia. In infants or small children with type 3 (severe) vWD, excessive bruising and even joint bleeding (due to very low levels of factor VIII) can mimic hemophilia A.
Laboratory evaluation for vWD requires several assays to quantitate vWF and characterize its structure and function. Many variables affect vWF assay results, including the patient’s ABO blood type. Persons of blood group AB have 60% to 70% higher vWF levels than those of blood group O. Thus, some laboratories interpret vWF levels referenced to specific normal ranges for blood types.
Clinical conditions and disorders with elevated vWF levels include pregnancy (third trimester), collagen vascular disorders, following surgery, in liver disease, and in disseminated intravascular coagulation. Low levels are seen in hypothyroidism and days 1 to 4 of the menstrual cycle.
Symptoms are modified by medications like aspirin or nonsteroidal antiinflammatory drugs (NSAIDs), which can exacerbate the bleeding; oral contraceptives can decrease the bleeding in women with vWD by increasing vWF levels. vWF levels in African American women are 15% higher than in white women. Clinical symptoms and family history are important for establishing the diagnosis of vWD, and a single test is sometimes not sufficient to rule out the diagnosis.
Initial work-up should include a complete blood count, aPTT, PT, fibrinogen level, or thrombin time. These tests do not rule out vWD but help to rule out thrombocytopenia or factor deficiency as the cause for bleeding. The closure times on the PFA-100, which has replaced the bleeding time as a screening test in some centers, may be prolonged. The aPTT in vWD is only abnormal when factor VIII is sufficiently reduced.
Specific tests for vWD include ristocetin cofactor assay, a factor VIII activity, and vWF antigen (vWF Ag) assay. The Ristocetin cofactor activity measures induced binding of vWF to platelet glycoprotein Ib and is the best functional assay of vWF activity. Multimer analysis is done by agarose gel electrophoresis using anti-vWF polyclonal antibody and is available at reference laboratories.
In type I vWD, the vWF is subnormal in amount, with normal multimer structure. Those with types 2A and 2B vWD lack the HMW multimers. In type 2B, the vWF has a heightened affinity for platelets, often resulting in some degree of thrombocytopenia from platelet aggregation. A useful laboratory test for type 2B is the low-dose ristocetin-induced platelet aggregation (RIPA) assay.
In type 3 (severe) vWD, the affected person has inherited a gene for type I vWD from each parent, resulting in very low levels (3%) of vWF (and low factor VIII, because there is no vWF to protect factor VIII from proteolytic degradation). Less commonly, a person with type 3 is doubly heterozygous. Table 4 provides a quick overview of the laboratory findings in the different variants of vWD.
Clinical Variants of von Willebrand Disease
Abbreviations: Ag = antigen; RIPA = ristocetin-induced platelet aggregation; vWF = von Willebrand factor.
In type 1 vWD (with subnormal levels of normally functioning vWF), the treatment of choice is DDAVP, which causes a rapid release of vWF from storage sites. It can be given intravenously or by the intranasal route. The recommended dose for IV use is 0.3 µg/kg, given in saline over 10 minutes. Most persons with type 1 vWD have a two- to four-fold increase in plasma levels of vWF within 15 to 30 minutes following infusion. The IV route is often used for surgical coverage or for a severe bleeding episode requiring hospitalization. When necessary, repeat doses may be given at 12- to 24-hour intervals. Tachyphylaxis is less commonly seen in vWD patients than in hemophilia patients. It is important to monitor free water intake following DDAVP administration because it can cause hyponatremia and seizures.
The concentrated form of desmopressin for intranasal use (Stimate nasal spray) may be used. The recommended dosage is one 150-µg spray for patients who weigh less than 50 kg and two sprays (one in each nostril) for those who weigh more than 50 kg. Some young women with menorrhagia have benefited from its use at the onset of menses, with a second dose after 24 hours. Others have used it approximately 45 minutes before invasive dentistry, with good results.
In the type 2 variants (vWF produced is abnormal), desmopressin can cause an increase in abnormal vWF. Although some persons with type 2A might respond, desmopressin is seldom useful in type 2 and might even be contraindicated (as in type 2B, where it can exacerbate the thrombocytopenia).
In type 3 vWD, desmopressin is ineffective because there is no vWF to be released from storage sites. For type 3 patients and in persons with type 1 vWD who do not respond adequately to desmopressin, an intermediate-purity plasma-derived concentrate rich in the hemostatically effective HMW multimers of vWF (such as Humate P) should be used to treat moderately severe or severe bleeding episodes and for before surgery.
As in hemophilia, antifibrinolytics are an effective adjunctive treatment for invasive dental procedures or other bleeding in the oropharyngeal cavity. These may be effective even when used alone in some vWD women with menorrhagia. For epistaxis, Nosebleed QR, a hydrophilic powder, can help.
vWF (and factor VIII) levels increase during the third trimester of pregnancy, and women with type 1 vWD have a decrease in bruising or other bleeding symptoms. However, those with type 2 vWD (abnormal vWF) and type 3 (no vWF) have no change in the bleeding tendency. Even in type 1 vWD, vWF levels fall following delivery, so treatment (with IV desmopressin or Humate P) may be needed.
Acquired von Willebrand Disease
Acquired vWD occurs in persons who do not have a lifelong bleeding disorder. Conditions associated with acquired vWD include underlying autoimmune disease (lymphoproliferative disorders, myeloproliferative disorders, or plasma cell dyscrasias), valvular and congenital heart disease, Wilms’ tumor, chronic renal failure, and hypothyroidism. The mechanism of acquired vWD is unknown.
Medications such as valproic acid can also cause vWD. Removal of the underlying condition often corrects the vWF. Desmopressin, Humate P, recombinant factor VIIa, or plasma exchange may be tried, if necessary, to treat bleeding.
Rare Bleeding Disorders
The rare bleeding disorders account for 3% to 5% of inherited coagulation deficiencies, other than factor VIII, factor IX, or vWF deficiencies. They are autosomal recessive and affect both sexes. The prevalence of rare bleeding disorders ranges from 1:500,000 to 1:2,000,000. Bleeding manifestations are restricted to persons who are homozygotes or compound heterozygotes. Rare bleeding disorders are common in countries such as Iran, where consanguineous marriages are customary. Ashkenazi Jews are particularly affected by factor XI deficiency. Deficiency of factor XII is a risk factor for thrombosis, but not for bleeding. Most cases of rare bleeding disorders are identified by abnormal screening tests coupled with specific factor assays.
Factor concentrates (recombinant or plasma derived) are available for some of the deficiencies (mostly in Europe, but not in the United States). Fibrogammin P, a plasma-derived virally purified FXIII concentrate, is now licensed and commercially available in the United States under the trade name of Corifact. In addition, a Phase III clinical trial for Recombinant FXIII is now ongoing to evaluate its safety and efficacy in the treatment of congential FXIII subunit A deficiency. The advantages of concentrates are pathogen safety and small volume. The use of antifibrinolytics and fibrin glue as adjunct therapy for bleeding manifestations is encouraged. Table 5 lists the inheritance, frequency, manifestations, and treatments of the rare bleeding disorders.
Rare Bleeding Disorders: Inheritance, Clinical Features, and Treatment
Abbreviations: AD = autosomal dominant; aPTT = activated partial thromboplastin time; AR = autosomal recessive; CNS = central nervous system; FFP = fresh frozen plasma; FI = fibrinogen; PCC = prothrombin complex concentrate; PT = prothrombin time; TT = thrombin time.
2 Not available in the United States.
- Available in Europe.
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