Patrick F. Fogarty, MD
Tracy Minichiello, MD
In assessing patients for defects of hemostasis, the clinical context must be considered carefully (Table 14–1). Heritable defects are suggested by bleeding that begins in infancy or childhood, is recurrent, and occurs at multiple anatomic sites, although many other patterns of presentation are possible. Acquired disorders of hemostasis more typically are associated with bleeding that begins later in life and may be relatable to introduction of medications (eg, agents that affect platelet activity) or to onset of underlying medical conditions (such as renal failure or myelodysplasia), or may be idiopathic. Importantly, however, a sufficient hemostatic challenge (such as major trauma) may produce excessive bleeding even in individuals with completely normal hemostasis.
Table 14–1. Evaluation of the bleeding patient.
Fogarty PF et al. Disorders of Hemostasis I: Coagulation. In: Rodgers GP et al (editors). The Bethesda Handbook of Clinical Hematology, 3rd ed. Philadelphia: Lippincott Williams and Wilkins, 2013.
The causes of thrombocytopenia are shown in Table 14–2. The age of the patient and presence of any comorbid conditions may help direct the diagnostic work-up.
Table 14–2. Causes of thrombocytopenia.
The risk of spontaneous bleeding (including petechial hemorrhage and bruising) does not typically increase appreciably until the platelet count falls below 10,000–20,000/mcL, although patients with dysfunctional platelets may bleed with higher platelet counts. Suggested platelet counts to prevent spontaneous bleeding or to provide adequate hemostasis around the time of invasive procedures are found in Table 14–3.
DECREASED PLATELET PRODUCTION
Bone marrow failure states may be congenital or acquired.
Most congenital marrow failure disorders present in childhood.
Congenital conditions that cause thrombocytopenia include amegakaryocytic thrombocytopenia, the thrombocytopenia-absent radius (TAR) syndrome, and Wiskott-Aldrich syndrome; these disorders usually feature isolated thrombocytopenia, whereas patients with Fanconi anemia and dyskeratosis congenita typically have depressions in other blood cell counts as well.
Acquired causes of bone marrow failure leading to thrombocytopenia include acquired aplastic anemia, myelodysplastic syndrome (MDS), and acquired amegakaryocytic thrombocytopenia. Unlike aplastic anemia, MDS is more common among older patients.
Acquired aplastic anemia typically presents with reductions in multiple blood cell lines; a bone marrow biopsy reveals hypocellularity. Myelodysplasia may also present as cytopenias with variable marrow cellularity, at times mimicking aplastic anemia; however, the presence of macrocytosis, ringed sideroblasts on iron staining of the bone marrow aspirate, dysplasia of hematopoietic elements, orcytogenetic abnormalities (especially monosomy 5 or 7, and trisomy 8) are more suggestive of MDS.
Adult patients with acquired amegakaryocytic thrombocytopenia have isolated thrombocytopenia and reduced or absent megakaryocytes in the bone marrow, which (along with failure to respond to immunomodulatory regimens typically administered in immune thrombocytopenia [ITP]) distinguishes them from patients with ITP.
Treatment is varied but may include blood product support, blood cell growth factors, androgens, and (some cases) allogeneic hematopoietic progenitor cell transplantation.
Patients with severe aplastic anemia are treated with allogeneic hematopoietic progenitor cell transplantation, which is the preferred therapy for patients younger than age 40 who have an HLA-matched sibling donor (see Chapter 13), or with immunosuppression, which is the preferred therapy for older patients and those who lack an HLA-matched sibling donor. The thrombopoietin receptor agonist eltrombopag has been shown to induce multilineage responses in selected patients with refractory severe aplastic anemia.
Treatment of thrombocytopenia due to MDS, if clinically significant bleeding is present or if the risk of bleeding is high, is limited to chronic transfusion of platelets in most instances (Table 14–3). Newer immunomodulatory agents such as lenalidomide do not produce increases in the platelet count in most patients. Use of the thrombopoietin receptor agonists, eltrombopag and romiplostim, in patients with MDS is being evaluated in clinical trials.
Table 14–3. Desired platelet count ranges.
Akhtari M. When to treat myelodysplastic syndromes. Oncology (Williston Park). 2011 May;25(6):480–6. [PMID: 21717901]
Kantarjian H et al. Safety and efficacy of romiplostim in patients with lower-risk myelodysplastic syndrome and thrombocytopenia. J Clin Oncol. 2010 Jan 20;28(3):437–44. [PMID: 20008626]
Marsh JC et al. Management of the refractory aplastic anemia patient: what are the options? Blood. 2013 Nov 21;122(22):3561–7. [PMID: 24052548]
Olnes MJ et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012 Jul 5;367(1):11–9. Erratum in: N Engl J Med. 2012 Jul 19;367(3):284. [PMID: 22762314]
Replacement of the normal bone marrow elements by leukemic cells, myeloma, lymphoma, or other tumors or by infections (such as mycobacterial disease or ehrlichiosis) may cause thrombocytopenia; however, abnormalities in other blood cell lines are also usually present. These entities are easily diagnosed after examining the bone marrow biopsy and aspirate or determining the infecting organism from an aspirate specimen. Treatment of thrombocytopenia is directed at eradication of the underlying infiltrative disorder, but platelet transfusion may be required if clinically significant bleeding is present.
Chemotherapeutic agents and irradiation may lead to thrombocytopenia by direct toxicity to megakaryocytes, hematopoietic progenitor cells, or both. The severity and duration of chemotherapy-induced depressions in the platelet count are determined by the specific regimen used, although the platelet count typically resolves more slowly following a chemotherapeutic insult than does neutropenia or anemia, especially if multiple cycles of treatment have been given. Until recovery occurs, patients may be supported with transfused platelets if bleeding is present or the risk of bleeding is high (Table 14–3). Clinical trials to determine the role of the platelet growth factors eltrombopag and romiplostim in the treatment of chemotherapy-induced thrombocytopenia have not shown clinically significant responses in the majority of treated patients.
Thrombocytopenia, typically in concert with anemia, may be observed when a deficiency of folate (that may accompany alcoholism) or vitamin B 12 is present (concomitant neurologic findings are common). In addition, thrombocytopenia rarely can occur in very severe iron deficiency. Replacing the deficient vitamin or mineral results in improvement in the platelet count.
Masoodi I et al. Hemorrhagic manifestation of megaloblastic anemia: report of two cases and literature review. Blood Coagul Fibrinolysis. 2011 Apr;22(3):234–5. [PMID: 21297452]
Cyclic thrombocytopenia is a very rare disorder that produces cyclic oscillations of the platelet count, usually with a periodicity of 3–6 weeks. The exact pathophysiologic mechanisms responsible for the condition may vary from patient to patient. Severe thrombocytopenia and bleeding typically occur at the platelet nadir. Oral contraceptive medications, androgens, azathioprine, and thrombopoietic growth factors have been used successfully in the management of cyclic thrombocytopenia.
INCREASED PLATELET DESTRUCTION
Assess for any new causative medications and HIV and hepatitis C infections.
ITP is a diagnosis of exclusion.
ITP is an autoimmune condition in which pathogenic antibodies bind platelets, resulting in accelerated platelet clearance. Contrary to the historical view of the disorder, it is now recognized that many patients with ITP also lack appropriate compensatory platelet production. The disorder is primary and idiopathic in most adult patients, although it can be associated with connective tissue disease (such as lupus), lymphoproliferative disease (such as lymphoma), medications (see below), and infections (such as hepatitis C virus and HIV infections). Targets of antiplatelet antibodies include glycoproteins IIb/IIIa and Ib/IX on the platelet membrane, although antibodies are demonstrable in only two-thirds of patients. In addition to production of antiplatelet antibodies, HIV and hepatitis C virus may lead to thrombocytopenia through additional mechanisms (for instance, by direct suppression of platelet production [HIV] and cirrhosis-related splenomegaly [hepatitis C virus]).
Mucocutaneous bleeding manifestations may be present, depending on the platelet count. Spontaneous bruising , nosebleeds, gingival bleeding, or other types of hemorrhage generally do not occur until the platelet count has fallen below 20,000–30,000/mcL. Individuals with secondary ITP (such as due to collagen vascular disease, HIV or HCV infection, or lymphoproliferative malignancy) may have additional disease-specific findings.
Typically, patients have isolated thrombocytopenia. If bleeding has occurred, anemia may also be present. Hepatitis B and C viruses and HIV infections should be excluded by serologic testing. Bone marrow should be examined in patients with unexplained cytopenias, in patients older than 60 years, or in those who did not respond to primary ITP-specific therapy. Megakaryocyte abnormalities and hypocellularity or hypercellularity are not characteristic of ITP. If there are clinical findings suggestive of a lymphoproliferative malignancy, a CT scan should be performed. In the absence of such findings, otherwise asymptomatic patients with unexplained isolated thrombocytopenia of recent onset may be considered to have ITP.
Only individuals with platelet counts < 20,000–30,000/mcL or those with significant bleeding should be treated; the remainder may be monitored serially for progression. The mainstay of initial treatment of new-onset primary ITP is a short course of corticosteroids with or without intravenous immunoglobulin (IVIG) or anti-D (WinRho) (Figure 14–1). Responses are generally seen within 3–5 days of initiating treatment. Platelet transfusions may be given concomitantly if active bleeding is present. The addition of the monoclonal anti-B cell antibody rituximab to corticosteroids as first-line treatment may improve the initial response rate, but is associated with increased toxicity and is not regarded as standard in most centers.
Figure 14–1. Management of immune thrombocytopenia (ITP).
Although over two-thirds of patients with ITP respond to initial treatment, most relapse following reduction of the corticosteroid dose. Patients with a persistent platelet count < 30,000/mcL or clinically significant bleeding are appropriate candidates for second-line treatments (Figure 14–1). These treatments are chosen empirically, bearing in mind potential toxicities and the patient’ s preference. Anti-D (WinRho) or IVIG temporarily increases platelet counts (duration, 3 weeks or longer), although serial anti-D treatment (platelet counts < 30,000/mcL) may allow adult patients to delay or avoid splenectomy. Rituximab leads to clinical responses in about 50% of adults with corticosteroid-refractory chronic ITP, which decrease to about 20% at 5 years. Romiplostim (administered subcutaneously weekly) and eltrombopag (taken orally daily) are approved for use in adult patients with chronic ITP who have not responded durably to corticosteroids, IVIG, or splenectomy and must be taken indefinitely to maintain the platelet response. Splenectomy has a durable response rate of over 65% and may be considered for cases of severe thrombocytopenia that fail to respond durably to initial treatment or are refractory to second-line agents; patients should receive pneumococcal, Haemophilus influenzae type b, and meningococcal vaccination at least 2 weeks before the procedure. If available, laparoscopic splenectomy is preferred. Additional treatments for ITP are found in Figure 14–1.
The goals of management of pregnancy-associated ITP are a platelet count of 10,000–30,000/mcL in the first trimester, > 30,000/mcL during the second or third trimester, and > 50,000/mcL prior to cesarean section or vaginal delivery. Moderate-dose oral prednisone or intermittent infusions of IVIG are standard. Splenectomy is reserved for failure to respond to these therapies and may be performed in the first or second trimester.
For thrombocytopenia associated with HIV or hepatitis C virus, treatment of either infection leads to an amelioration in the platelet count in most cases; refractory thrombocytopenia may be treated with infusion of IVIG or anti-D (HIV and hepatitis C virus), splenectomy (HIV), or interferon-alpha or eltrombopag (hepatitis C virus, including eradication). Treatment with corticosteroids is not recommended in hepatitis C virus infection.
When to Refer
Chronic thrombocytopenia will develop in most adult patients with newly diagnosed ITP. All patients with ITP should be referred to a subspecialist for evaluation at the time of diagnosis.
When to Admit
Patients with major hemorrhage or very severe thrombocytopenia associated with bleeding should be admitted and monitored in-hospital until the platelet count has risen to > 20,000–30,000/mcL and hemodynamic stability has been achieved.
Afdhal NH et al; ELEVATE Study Group. Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med. 2012 Aug 23;367(8):716–24. [PMID: 22913681]
Gudbrandsdottir S et al. Rituximab and dexamethasone vs dexamethasone monotherapy in newly diagnosed patients with primary immune thrombocytopenia. Blood. 2013 Mar 14;121(11):1976–81. [PMID: 23293082]
Provan D et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010 Jan 14;115(2):168–86. [PMID: 19846889]
Microangiopathic hemolytic anemia and thrombocytopenia, in the absence of another plausible explanation, are sufficient for the diagnosis of TMA.
Fever, neurologic abnormalities, and kidney disease may occur concurrently but are not required for diagnosis.
Kidney disease occurs in hemolytic-uremic syndrome.
The thrombotic microangiopathies (TMAs) include thrombotic thrombocytopenic purpura (TTP) and the hemolytic-uremic syndrome (HUS). These disorders are characterized by thrombocytopenia, due to the incorporation of platelets into thrombi in the microvasculature, and microangiopathic hemolytic anemia, which results from shearing of erythrocytes in the microcirculation.
In idiopathic TTP, autoantibodies against the ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin type 1 repeat, member 13) molecule, also known as the von Willebrand factor cleaving protease (vWFCP), leads to accumulation of ultra-large von Willebrand factor (vWF) multimers that bridge platelets and facilitate excessive platelet aggregation, leading to TTP. Atypical HUS is a chronic disorder that typically leads to kidney disease. Patients with atypical HUS may have genetic defects in proteins that regulate complement activity, such as factor H. Damage to endothelial cells—such as the damage that occurs in endemic HUS due to presence of toxins from Escherichia coli (especially type O157:H7 or O145) or in the setting of cancer, hematopoietic stem cell transplantation, or HIV infection—may also lead to TMA. Certain drugs (eg, cyclosporine, quinine, ticlopidine, clopidogrel, mitomycin C, and bleomycin) have been associated with the development of TMA, possibly by promoting injury to endothelial cells, although inhibitory antibodies to ADAMTS-13 also have been demonstrated in some cases.
Microangiopathic hemolytic anemia and thrombocytopenia are presenting signs in all patients with TTP and most patients with HUS; in a subset of patients with HUS, the platelet count remains in the normal range. Only approximately 25% of patients with TMA manifest all components of the so-called pentad of findings (microangiopathic hemolytic anemia, thrombocytopenia, fever, kidney disease, and neurologic system abnormalities) (Table 14–4). Most patients (especially children) with HUS have a recent or current diarrheal illness. Neurologic manifestations, including headache, somnolence, delirium, seizures, paresis, and coma, may result from deposition of microthrombi in the cerebral vasculature. Atypical HUS typically presents in childhood.
Table 14–4. Presentation and management of thrombotic microangiopathies.
Laboratory features of TMA include those associated with microangiopathic hemolytic anemia (anemia, elevated lactate dehydrogenase [LD], elevated indirect bilirubin, decreased haptoglobin, reticulocytosis, negative direct antiglobulin test, and schistocytes on the blood smear); thrombocytopenia; elevated creatinine; positive stool culture for E coli O157:H7 or stool assays for Shiga-toxin producing E coli to detect non-O157:H7 such as E coli O145 (HUS only); reductions in vWFCP activity (idiopathic TTP); and mutations of genes encoding complement proteins (atypical HUS; specialized laboratory assessment). Notably, routine coagulation studies are within the normal range in most patients with TMA.
Immediate administration of plasma exchange is essential in most cases due to the mortality rate of > 95% without treatment. With the exception of children or adults with endemic diarrhea-associated HUS, who generally recover with supportive care only, plasma exchange must be initiated as soon as the diagnosis of TMA is suspected. Plasma exchange usually is administered once daily until the platelet count and LD have returned to normal for at least 2 days, after which the frequency of treatments may be tapered slowly while the platelet count and LD are monitored for relapse. In cases of insufficient response to once-daily plasma exchange, twice-daily treatments should be given. Fresh frozen plasma (FFP) may be administered if immediate access to plasma exchange is not available or in cases of familial TMA. Platelet transfusions are contraindicated in the treatment of TMAs due to reports of worsening TMA, possibly due to propagation of platelet-rich microthrombi. In cases of documented life-threatening bleeding, however, platelet transfusions may be given slowly and after plasma exchange is underway. Red blood cell transfusions may be administered in cases of clinically significant anemia. Hemodialysis should be considered for patients with significant renal impairment.
In cases of relapse following initial treatment, plasma exchange should be reinstituted. If ineffective, or in cases of primary refractoriness, second-line treatments may be considered including rituximab, corticosteroids, IVIG, vincristine, cyclophosphamide, and splenectomy.
Cases of atypical HUS may respond to plasma infusion initially, and serial infusions of the anti-complement C5 antibody eculizumab have produced sustained remissions in some patients. If irreversible renal impairment has occurred, hemodialysis or renal transplantation may be necessary.
When to Refer
Consultation by a hematologist or transfusion medicine specialist familiar with plasma exchange is required at the time of presentation. Patients with refractory or relapsing TMA require ongoing care by a subspecialist.
When to Admit
All patients with newly suspected or diagnosed TMA should be hospitalized initially.
Caramazza D et al. Relapsing or refractory idiopathic thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: the role of rituximab. Transfusion. 2010 Dec;50(12):2753–60. [PMID: 20576013]
Deford CC et al. Multiple major morbidities and increased mortality during long-term follow-up after recovery from thrombotic thrombocytopenic purpura. Blood. 2013 Sep 19;122(12):2023–9. [PMID: 23838348]
Legendre CM et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013 Jun 6;368(23):2169–81. [PMID: 23738544]
Thrombocytopenia within 5–10 days of exposure to heparin.
Decline in baseline platelet count of 50% or greater.
Thrombosis occurs in 50% of cases; bleeding is uncommon.
Heparin-induced thrombocytopenia (HIT) is an acquired disorder that affects approximately 3% of patients who are exposed to unfractionated heparin and 0.6% of patients who are exposed to low-molecular-weight heparin (LMWH). The condition results from formation of IgG antibodies to heparin-platelet factor 4 (PF4) complexes; the antibodies then bind platelets, which activates them. Platelet activation leads to both thrombocytopenia and a pro-thrombotic state.
Patients are usually asymptomatic, and due to the pro-thrombotic nature of HIT, bleeding usually does not occur. Thrombosis (at any venous or arterial site), however, may be detected in up to 50% of patients, up to 30 days post-diagnosis.
A presumptive diagnosis of HIT is made when new-onset thrombocytopenia is detected in a patient (frequently a hospitalized patient) within 5–10 days of exposure to heparin; other presentations (eg, rapid-onset HIT) are less common. A decline of ≥ 50% or more from the baseline platelet count is typical. The 4T score (http://www.qxmd.com/calculate-online/hematology/hit-heparin-induced-thrombocytopenia-probability) is a clinical prediction rule that may assist in assessment of pretest probability for HIT, although low scores have been shown to be more predictive than intermediate or high scores. Confirmation of the diagnosis is through a positive PF4-heparin antibody enzyme-linked immunosorbent assay (ELISA) or functional assay (such as serotonin release assay), or both. The magnitude of a positive ELISA result correlates with the clinical probability of HIT.
Treatment should be initiated as soon as the diagnosis of HIT is suspected, before results of laboratory testing is available.
Management of HIT (Table 14–5) involves the immediate discontinuation of all forms of heparin.
Table 14–5. Management of suspected or proven HIT.
If thrombosis has not already been detected, duplex Doppler ultrasound of the lower extremities should be performed to rule out subclinical deep venous thrombosis. Despite thrombocytopenia, platelet transfusions are rarely necessary. Due to the substantial frequency of thrombosis among HIT patients, an alternative anticoagulant, typically a direct thrombin inhibitor (DTI) such as argatroban should be administered immediately. The DTI should be continued until the platelet count has recovered to at least 100,000/mcL, at which point treatment with a vitamin K antagonist (warfarin) may be initiated. The DTI should be continued until therapeutic anticoagulation with the vitamin K antagonist has been achieved (international normalized ratio [INR] of 2.0–3.0) due to the warfarin effect; the infusion of argatroban must be temporarily discontinued for 2 hours before the INR is obtained so that it reflects the anticoagulant effect of warfarin alone. Warfarin is contraindicated as initial treatment of HIT because of its potential to transiently worsen hypercoagulability. Some clinicians endorse use of the subcutaneous indirect anti-Xa inhibitor fondaparinux for initial treatment of HIT, but the practice is not yet standard in most centers. In all patients with HIT, warfarin subsequently should be continued for at least 30 days, due to a persistent risk of thrombosis even after the platelet count has recovered, whereas in patients in whom thrombosis has been documented, anticoagulation with warfarin should continue for 3–6 months.
Subsequent exposure to heparin should be avoided in all patients with a prior history of HIT, if possible. If its use is regarded as necessary for a procedure, it should be withheld until PF4-heparin antibodies are no longer detectable by ELISA (usually as of 100 days following an episode of HIT), and exposure should be limited to the shortest time period possible.
When to Refer
Due to the tremendous thrombotic potential of the disorder and the complexity of use of the DTI, all patients with HIT should be evaluated by a hematologist.
When to Admit
Most patients with HIT are hospitalized at the time of detection of thrombocytopenia. Any outpatient in whom HIT is suspected should be admitted because the DTIs must be administered by continuous intravenous infusion.
Cuker A. Heparin-induced thrombocytopenia: present and future. J Thromb Thrombolysis. 2011 Apr;31(3):353–66. [PMID: 21327506]
Cuker A et al. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood. 2012 Nov 15;120(20):4160–7. [PMID: 22990018]
Warkentin TE et al. Heparin-induced thrombocytopenia in medical surgical critical illness. Chest. 2013 Sep;144(3):848–58. [PMID: 23722881]
A frequent cause of thrombocytopenia in hospitalized patients.
Prolonged activated partial thromboplastin time and prothrombin time.
Thrombocytopenia and decreased fibrinogen levels.
Disseminated intravascular coagulation (DIC) results from uncontrolled local or systemic activation of coagulation, which leads to depletion of coagulation factors and fibrinogen and to thrombocytopenia as platelets are activated and consumed.
The numerous disorders that are associated with DIC include sepsis (in which coagulation is activated by presence of lipopolysaccharide) as well as cancer, trauma, burns, or pregnancy-associated morbidity (in which tissue factor is released). Aortic aneurysm and cavernous hemangiomas may promote DIC by leading to vascular stasis, and snake bites may result in DIC due to the introduction of exogenous toxins.
Bleeding in DIC usually occurs at multiple sites, such as intravenous catheters or incisions, and may be widespread (purpura fulminans). Malignancy-related DIC may manifest principally as thrombosis (Trousseau syndrome).
In early DIC, the platelet count and fibrinogen levels may remain within the normal range, albeit reduced from baseline levels. There is progressive thrombocytopenia (rarely severe), prolongation of the activated partial thromboplastin time (aPTT) and prothrombin time (PT), and low levels of fibrinogen. D-dimer levels typically are elevated due to the activation of coagulation and diffuse cross-linking of fibrin. Schistocytes on the blood smear, due to shearing of red cells through the microvasculature, are present in 10–20% of patients. Laboratory abnormalities in the HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), a severe form of DIC with a particularly high mortality rate that occurs in peripartum women, include elevated liver transaminases and (many cases) kidney injury due to gross hemoglobinuria and pigment nephropathy. Malignancy-related DIC may feature normal platelet counts and coagulation studies.
The underlying causative disorder must be treated (eg, antimicrobials, chemotherapy, surgery, or delivery of conceptus [see below]). If clinically significant bleeding is present, hemostasis must be achieved (Table 14–6).
Table 14–6. Management of DIC.
Blood products should be administered only if clinically significant hemorrhage has occurred or is thought likely to occur without intervention (Table 14–6). The goal of platelet therapy for most cases is > 20,000/mcL or > 50,000/mcL for serious bleeding, such as intracranial bleeding. FFP should be given only to patients with a prolonged aPTT and PT and significant bleeding; 4 units typically are administered at a time, and the posttransfusion platelet count should be documented. Cryoprecipitate may be given for bleeding and fibrinogen levels < 80–100 mg/dL. The PT, aPTT, fibrinogen, and platelet count should be monitored at least every 6 hours in acutely ill patients with DIC.
In some cases of refractory bleeding despite replacement of blood products, administration of low doses of heparin can be considered; it may help interfere with thrombin generation, which then could lead to a lessened consumption of coagulation proteins and platelets. An infusion of 6–10 units/kg/h (no bolus) may be used. Heparin, however, is contraindicated if the platelet count cannot be maintained at ≥ 50,000/mcL and in cases of central nervous system/gastrointestinal bleeding, placental abruption, and any other condition that is likely to require imminent surgery. Fibrinolysis inhibitors may be considered in some patients with refractory DIC.
The treatment of HELLP syndrome must include evacuation of the uterus (eg, delivery of a term or near-term infant or removal of retained placental or fetal fragments). Patients with Trousseau syndrome require treatment of the underlying malignancy or administration of unfractionated heparin or subcutaneous therapeutic-dose LMWH as treatment of thrombosis, since warfarin typically is ineffective at secondary prevention of thromboembolism in the disorder. Immediate initiation of chemotherapy (usually within 24 hours of diagnosis) is required for patients with acute promyelocytic leukemia (APL)–associated DIC, along with administration of blood products as clinically indicated.
When to Refer
Patients with diffuse bleeding that is unresponsive to administration of blood products should be evaluated by a hematologist.
When to Admit
Most patients with DIC are hospitalized when DIC is detected.
Levi M et al. Disseminated intravascular coagulation in infectious disease. Semin Thromb Hemost. 2010 Jun;36(4):367–77. [PMID: 20614389]
Martí-Carvajal AJ et al. Treatment for disseminated intravascular coagulation in patients with acute and chronic leukemia. Cochrane Database Syst Rev. 2011 Jun 15;(6):CD008562. [PMID: 21678379]
Singh B et al. Trends in the incidence and outcomes of disseminated intravascular coagulation in critically ill patients (2004–2010): a population-based study. Chest. 2013 May;143(5):1235–42. [PMID: 23139140]
Wada H et al. Diagnostic criteria and laboratory tests for disseminated intravascular coagulation. Expert Rev Hematol. 2012 Dec;5(6):643–52. [PMID: 23216594]
OTHER CONDITIONS CAUSING THROMBOCYTOPENIA
The mechanisms underlying drug-induced thrombocytopenia are thought in most cases to be immune, although exceptions exist (such as chemotherapy). Table 14–7 lists medications associated with thrombocytopenia. The typical presentation of drug-induced thrombocytopenia is severe thrombocytopenia and mucocutaneous bleeding 7–14 days after exposure to a new drug, although a range of presentations is possible. Discontinuation of the offending agent leads to resolution of thrombocytopenia within 7–10 days in most cases, but patients with severe thrombocytopenia should be given platelet transfusions with (immune cases only) or without IVIG.
Table 14–7. Selected medications causing drug-associated thrombocytopenia.
Posttransfusion purpura (PTP) is a rare disorder that features sudden-onset thrombocytopenia in an individual who recently has received transfusion of red cells, platelets, or plasma within 1 week prior to detection of thrombocytopenia. Antibodies against the human platelet antigen Pl A1 are detected in most individuals with PTP. Patients with PTP almost universally are either multiparous women or persons who have received transfusions previously. Severe thrombocytopenia and bleeding is typical. Initial treatment consists of administration of IVIG (1 g/kg/d for 2 days) which should be administered as soon as the diagnosis is suspected. Platelets are not indicated unless severe bleeding is present, but if they are to be administered, HLA-matched platelets are preferred. A second course or IVIG, plasma exchange, corticosteroids, or splenectomy may be used in case of refractoriness. Pl A1-negative or washed blood products are preferred for subsequent transfusions.
von Willebrand disease (vWD) type 2B leads to chronic, characteristically mild to moderate thrombocytopenia via an abnormal vWF molecule that binds platelets with increased affinity, resulting in aggregation and clearance.
At any given time, one-third of the platelet mass is sequestered in the spleen. Splenomegaly, due to a variety of conditions, may lead to thrombocytopenia of variable severity. Whenever possible, treatment of the underlying disorder should be pursued, but splenectomy, splenic embolization, or splenic irradiation may be considered in selected cases.
Gestational thrombocytopenia results from progressive expansion of the blood volume that typically occurs during pregnancy, leading to hemodilution. Cytopenias result, although production of blood cells is normal or increased. Platelet counts < 100,000/mcL, however, are observed in < 10% of pregnant women in the third trimester; decreases to < 70,000/mcL should prompt consideration of pregnancy- related ITP (see above) as well as preeclampsia or a pregnancy-related thrombotic microangiopathy.
Both immune- and platelet production–mediated defects are possible, and there may be significant overlap with concomitant DIC (see above). In either case, the platelet count typically improves with effective antimicrobial treatment or after the infection has resolved. In some critically ill patients, a defect in immunomodulation may lead to bone marrow macrophages (histiocytes) engulfing cellular components of the marrow in a process also called hemophagocytosis. The phenomenon typically resolves with resolution of the infection, but with certain infections (Epstein Barr virus) immunosuppression may be required. Hemophagocytosis also may arise in the setting of malignancy, in which case the disorder is usually unresponsive to treatment with immunosuppression.
Pseudothrombocytopenia results from EDTA anticoagulant-induced platelet clumping; the phenomenon typically disappears when blood is collected in a tube containing citrate anticoagulant.
Bockenstedt PL. Thrombocytopenia in pregnancy. Hematol Oncol Clin North Am. 2011 Apr;25(2):293–310. [PMID: 21444031]
Perdomo J et al. Quinine-induced thrombocytopenia: drug-dependent GPIb/IX antibodies inhibit megakaryocyte and proplatelet production in vitro. Blood. 2011 Jun 2;117(22):5975–86. [PMID: 21487107]
QUALITATIVE PLATELET DISORDERS
CONGENITAL DISORDERS OF PLATELET FUNCTION
Usually diagnosed in childhood.
Family history usually is positive.
May be diagnosed in adulthood when there is excessive bleeding.
Heritable qualitative platelet disorders are far less common than acquired disorders of platelet function (see below) and lead to variably severe bleeding, often beginning in childhood. Occasionally, however, disorders of platelet function may go undetected until later in life when excessive bleeding occurs following a sufficient hemostatic insult. Thus, the true incidence of hereditary qualitative platelet disorders is unknown.
Bernard-Soulier syndrome (BSS) is a rare, autosomal recessive bleeding disorder that is due to reduced or abnormal platelet membrane expression of glycoprotein Ib/IX (vWF receptor).
Glanzmann thrombasthenia results from a qualitative or quantitative abnormality in glycoprotein IIb/IIIa receptors on the platelet membrane, which are required to bind fibrinogen and vWF, both of which bridge platelets during aggregation. Inheritance is autosomal recessive.
Under normal circumstances, activated platelets release the contents of platelet granules to reinforce the aggregatory response. Storage pool disease is caused by defects in release of alpha or dense (delta) platelet granules, or both (alpha-delta storage pool disease).
In patients with Glanzmann thrombasthenia, the onset of bleeding is usually in infancy or childhood. The degree of deficiency in IIb/IIIa may not correlate well with bleeding symptoms. Patients withstorage pool disease are affected by variable bleeding, ranging from mild and trauma-related to spontaneous.
In Bernard-Soulier syndrome, there are abnormally large platelets (approaching the size of red cells), moderate thrombocytopenia, and a prolonged bleeding time. Platelet aggregation studies show a marked defect in response to ristocetin, whereas aggregation in response to other agonists is normal; the addition of normal platelets corrects the abnormal aggregation. The diagnosis can be confirmed by platelet flow cytometry.
In Glanzmann thrombasthenia, platelet aggregation studies show marked impairment of aggregation in response to stimulation with typical agonists.
Storage pool disease describes defects in the number or content of platelet alpha or dense granules or both. The gray platelet syndrome comprises abnormalities of platelet alpha granules, thrombocytopenia, and marrow fibrosis. The blood smear shows agranular platelets, and the diagnosis is confirmed with electron microscopy.
Albinism-associated storage pool disease involves defective dense granules in disorders of oculocutaneous albinism, such as the Hermansky-Pudlak and Chediak-Higashi syndromes. Electron microscopy confirms the diagnosis.
Non–albinism-associated storage pool disease results from quantitative or qualitative defects in dense granules and is seen in Ehlers-Danlos and Wiskott-Aldrich syndromes, among others.
The Quebec platelet disorder comprises mild thrombocytopenia, an abnormal platelet factor V molecule, and a prolonged bleeding time. Patients typically experience moderate bleeding. Interestingly, platelet transfusion does not ameliorate the bleeding.
Patients have a prolonged bleeding time. Platelet aggregation studies characteristically show platelet dissociation following an initial aggregatory response, and electron microscopy confirms the diagnosis.
The mainstay of treatment (including periprocedural prophylaxis) is transfusion of normal platelets, although desmopressin acetate (DDAVP), antifibrinolytic agents, and recombinant human activated factor VII also have been used successfully.
Andrews RK et al. Bernard-Soulier syndrome: an update. Semin Thromb Hemost. 2013 Sep;39(6):656–62. [PMID: 23929303]
Lambert MP. What to do when you suspect an inherited platelet disorder. Hematology Am Soc Hematol Educ Program. 2011;2011:377–83. [PMID: 22160061]
ACQUIRED DISORDERS OF PLATELET FUNCTION
Platelet dysfunction is more commonly acquired than inherited; the widespread use of platelet-active medications accounts for most of the cases of qualitative defects (Table 14–8). In these cases, platelet inhibition typically declines within 5–10 days following discontinuation of the drug, and transfusion of platelets may be required if clinically significant bleeding is present.
Table 14–8. Causes of acquired platelet dysfunction.
DISORDERS OF COAGULATION
CONGENITAL DISORDERS OF COAGULATION
Hemophilia A: congenital deficiency of coagulation factor VIII.
Hemophilia B: congenital deficiency of coagulation factor IX.
Recurrent hemarthroses and arthropathy.
Risk of development of inhibitory antibodies to factor VIII or factor IX.
In many older patients, infection with HIV or hepatitis C virus from receipt of contaminated blood products.
The frequency of hemophilia A is 1 per 5000 live male births, whereas hemophilia B occurs in approximately 1 in 25,000 live male births. Inheritance is X-linked recessive, leading to affected males and carrier females. There is no race predilection. Testing is indicated for asymptomatic male infants with a hemophilic pedigree, for male infants with a family history of hemophilia who experience excessive bleeding, or for an otherwise asymptomatic adolescent or adult who experiences unexpected excessive bleeding with trauma or invasion.
Inhibitors to factor VIII will develop in approximately 30% of patients with hemophilia A, and inhibitors to factor IX will develop in < 5% of patients with hemophilia B.
A substantial proportion of older patients with hemophilia acquired infection with HIV or HCV or both in the 1980s due to exposure to contaminated factor concentrates and blood products.
Severe hemophilia presents in infant males or in early childhood with spontaneous bleeding into joints, soft tissues, or other locations. Spontaneous bleeding is rare in patients with mild hemophilia, but bleeding may occur with a significant hemostatic challenge (eg, surgery, trauma). Intermediate clinical symptoms are seen in patients with moderate hemophilia. Female carriers of hemophilia are usually asymptomatic.
Significant hemophilic arthropathy is usually avoided in patients who have received long-term prophylaxis with factor concentrate starting in childhood, whereas joint disease is common in adults who have experienced recurrent hemarthroses.
Inhibitor development to factor VIII or factor IX is characterized by bleeding episodes that are resistant to treatment with clotting factor VIII or IX concentrate, and by new or atypical bleeding.
Hemophilia is diagnosed by demonstration of an isolated reproducibly low factor VIII or factor IX activity level, in the absence of other conditions. If the aPTT is prolonged, it typically corrects upon mixing with normal plasma. A variety of mutations, including inversions, large and small deletions, insertions, missense mutations, and nonsense mutations may be causative. Depending on the level of residual factor VIII or factor IX activity and the sensitivity of the thromboplastin used in the aPTT coagulation reaction, the aPTT may or may not be prolonged (although it typically is markedly prolonged in severe hemophilia). Hemophilia is classified according to the level of factor activity in the plasma. Severe hemophilia is characterized by < 1% factor activity, mild hemophilia features > 5% factor activity, and moderate hemophilia features 1–5% factor activity. Female carriers may become symptomatic if significant lyonization has occurred favoring the defective factor VIII or factor IX gene, leading to factor VIII or factor IX activity level markedly < 50%.
In the presence of an inhibitor to factor VIII or factor IX, there is accelerated clearance of and suboptimal or absent rise in measured activity of infused factor, and the aPTT does not correct on mixing. The Bethesda assay measures the potency of the inhibitor.
Plasma-derived or recombinant factor concentrates are the mainstay of treatment. By the age of 4 years, most children with severe hemophilia have begun twice- or thrice-weekly infusions of factor to prevent the recurrent joint bleeding that otherwise would characterize the disorder and lead to severe musculoskeletal morbidity. Adults are frequently treated with factor concentrate as needed for bleeding episodes or prior to high-risk activities (Table 14–9). Patients with mild hemophilia A may respond to as-needed intravenous or intranasal treatment with DDAVP. Antifibrinolytic agents may be useful in cases of mucosal bleeding and are commonly used adjunctively, such as following dental procedures. Clinical trials of longer-acting FVIII and FIX molecules are underway. Delivery of a functional factor IX gene via viral vectors continues to be explored in gene therapy trials; early results among patients with severe hemophilia B show improvement in the baseline FIX level so as to reduce or eliminate the need for prophylactic infusions of FIX concentrate.
Table 14–9. Treatment of selected inherited bleeding disorders.
It may be possible to overcome low-titer inhibitors (< 5 Bethesda units [BU]) by giving larger doses of factor, whereas treatment of bleeding in the presence of a high-titer inhibitor (> 5 BU) requires infusion of an activated prothrombin complex concentrate or recombinant activated factor VII. Inhibitor tolerance induction, achieved by giving large doses (50–300 units/kg intravenously of factor VIII daily) for 6–18 months, succeeds in eradicating the inhibitor in 70% of patients with hemophilia A and in 30% of patients with hemophilia B. Patients with hemophilia B who receive inhibitor tolerance induction, however, are at risk for development of nephrotic syndrome and anaphylactic reactions, making eradication of their inhibitors less feasible. Additional immunomodulation may allow for eradication in selected inhibitor tolerance induction–refractory patients.
Highly active antiretroviral treatment is almost universally administered to individuals with HIV infection.
When to Refer
All patients with hemophilia should be seen regularly in a comprehensive hemophilia treatment center.
When to Admit
Berntorp E. Importance of rapid bleeding control in haemophilia complicated by inhibitors. Haemophilia. 2011 Jan;17(1):11–6. [PMID: 20565546]
Fogarty PF. Biological rationale for new drugs in the bleeding disorders pipeline. Hematology Am Soc Hematol Educ Program.2011;2011:397–404. [PMID: 22160064]
Fogarty PF et al. Hemophilia A and B. In: Kitchens CS et al (editors). Consultative Hemostasis and Thrombosis, 3rd ed. New York: Elsevier, 2013.
Gouw SC et al; PedNet and Research of Determinants of INhibitor development (RODIN) Study Group. Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study. Blood. 2013 May 16;121(20):4046–55. [PMID: 23553768]
Leissinger C et al. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med. 2011 Nov 3;365(18):1684–92. [PMID: 22047559]
Nathwani AC et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011 Dec 22;365(25):2357–65. [PMID: 22149959]
The most common inherited bleeding disorder.
von Willebrand factor aggregates platelets and prolongs the half-life of factor VIII.
vWF is an unusually large multimeric glycoprotein that binds to its receptor, platelet glycoprotein Ib, bridging platelets together and tethering them to the subendothelial matrix at the site of vascular injury. vWF also has a binding site for factor VIII, prolonging its half-life in the circulation.
Between 75% and 80% of patients with vWD have type 1. It is a quantitative abnormality of the vWF molecule that usually does not feature an identifiable causal mutation in the vWF gene.
Type 2 vWD is seen in 15–20% of patients with vWD. In type 2A or 2B vWD, a qualitative defect in the vWF molecule is causative. Type 2N and 2M vWD are due to defects in vWF that decrease binding to factor VIII or to platelets, respectively. Importantly, type 2N vWD clinically resembles hemophilia A, with the exception of a family history that shows affected females. Factor VIII activity levels are markedly decreased, and vWF activity and antigen (Ag) are normal. Type 2M vWD features a normal multimer pattern. Type 3 vWD is rare, and mutational homozygosity or double heterozygosity leads to undetectable levels of vWF and severe bleeding in infancy or childhood.
Patients with type 1 vWD usually have mild or moderate platelet-type bleeding (especially involving the integument and mucous membranes). Patients with type 2 vWD usually have moderate to severe bleeding that presents in childhood or adolescence.
In type 1 vWD, the vWF activity (by ristocetin co-factor assay) and Ag are mildly depressed, whereas the vWF multimer pattern is normal (Table 14–10). Laboratory testing of type 2A or 2B vWD typically shows a ratio of vWF Ag:vWF activity of approximately 2:1 and a multimer pattern that lacks the highest molecular weight multimers. Thrombocytopenia is common in type 2B vWD due to a gain-of-function mutation of the vWF molecule, which leads to increased binding to its receptor on platelets, resulting in clearance; a ristocetin-induced platelet aggregation (RIPA) study shows an increase in platelet aggregation in response to low concentrations of ristocetin. Except in the more severe forms of vWD that feature a significantly decreased factor VIII activity, the aPTT and PT in vWD are usually normal.
Table 14–10. Laboratory diagnosis of von Willebrand disease.
The treatment of vWD is summarized in Table 14–9. DDAVP is useful in the treatment of mild bleeding in most cases of type 1 and some cases of type 2 vWD. DDAVP causes release of vWF and factor VIII from storage sites, leading to increases in vWF and factor VIII twofold to sevenfold that of baseline levels. Cryoprecipitate should not be given due to lack of viral inactivation. Antifibrinolytic agents (eg, aminocaproic acid) may be used adjunctively for mucosal bleeding or procedures. Pregnant patients with vWD usually do not require treatment because of the natural physiologic increase in vWF levels (up to threefold that of baseline) that are observed by the time of delivery; however, if excessive bleeding is encountered, vWF-containing factor VIII concentrates may be given.
Abshire TC et al. Prophylaxis in severe forms of von Willebrand’s disease: results from the von Willebrand Disease Prophylaxis Network (VWD PN). Haemophilia. 2013 Jan;19(1):76–81. [PMID: 22823000]
Lipe BC et al. Von Willebrand disease in pregnancy. Hematol Oncol Clin North Am. 2011 Apr;25(2):335–58. [PMID: 21444034]
Rick ME. Von Willebrand Disease. In: Kitchens CS et al (editors). Consultative Hemostasis and Thrombosis, 3rd ed. New York: Elsevier, 2013.
Factor XI deficiency (sometimes referred to as hemophilia C) is inherited in an autosomal recessive manner, leading to heterozygous or homozygous defects. It is most prevalent among individuals of Ashkenazi Jewish descent. Levels of factor XI, while variably reduced, do not correlate well with bleeding symptoms. Mild bleeding is most common, and surgery or trauma may expose or worsen the bleeding tendency. FFP is the mainstay of treatment in locales where the plasma-derived factor XI concentrate is not available. Administration of adjunctive aminocaproic acid is regarded as mandatory for procedures or bleeding episodes involving the mucosa (Table 14–9).
Martín-Salces M et al. Review: Factor XI deficiency: review and management in pregnant women. Clin Appl Thromb Hemost. 2010 Apr;16(2):209–13. [PMID: 19049995]
Congenital deficiencies of clotting factors II, V, VII, and X are rare and typically are inherited in an autosomal recessive pattern. A prolongation in the PT (and aPTT for factor X and factor II deficiency) that corrects upon mixing with normal plasma is typical. The treatment of factor II deficiency is with a prothrombin complex concentrate; factor V deficiency is treated with infusions of FFP or platelets (which contain factor V in alpha granules); factor VII deficiency is treated with recombinant human activated factor VII at 15–30 mcg/kg every 4–6 hours; and infusions of FFP may be used to treat factor X deficiency.
Deficiency of factor XIII, a transglutamase that cross-links fibrin, characteristically leads to delayed bleeding that occurs hours to days after a hemostatic challenge (such as surgery or trauma). The condition is usually life-long, and spontaneous intracranial hemorrhages as well as recurrent pregnancy loss appear to occur with increased frequency in these patients compared with other congenital deficiencies. Cryoprecipitate or infusion of a plasma-derived factor XIII concentrate (available through a research study; appropriate for patients with A-subunit deficiency only) is the treatment of choice for bleeding or surgical prophylaxis.
Bereczky Z et al. Factor XIII and venous thromboembolism. Semin Thromb Hemost. 2011 Apr;37(3):305–14. [PMID: 21455864]
Peyvandi F et al. Rare bleeding disorders. Semin Thromb Hemost. 2009 Jun;35(4):345–7. [PMID: 19598062]
ACQUIRED DISORDERS OF COAGULATION
Spontaneous antibodies to factor VIII occasionally occur in adults without a prior history of hemophilia; the elderly and patients with lymphoproliferative malignancy or connective tissue disease, who are postpartum, or postsurgical are at highest risk. The clinical presentation typically includes extensive soft-tissue ecchymoses, hematomas, and mucosal bleeding, as opposed to hemarthrosis in congenital hemophilia A. The aPTT is typically prolonged and does not correct upon mixing; factor VIII activity is found to be low and a Bethesda assay reveals the titer of the inhibitor. Inhibitors of low titer (< 5 BU) may often be overcome by infusion of high doses of factor VIII concentrates, whereas high-titer inhibitors (> 5 BU) must be treated with serial infusions of activated prothrombin complex concentrates or recombinant human activated factor VII. Along with establishment of hemostasis by one of these measures, immunosuppressive treatment with corticosteroids and oral cyclophosphamide should be instituted; treatment with IVIG, rituximab, or plasmapheresis can be considered in refractory cases.
Knoebl P et al. Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). J Thromb Haemost. 2012 Apr;10(4):622–31. [PMID: 22321904]
Patients with antiphospholipid antibodies occasionally manifest specificity to coagulation factor II (prothrombin), leading typically to a severe hypoprothrombinemia and bleeding. Mixing studies may or may not reveal presence of an inhibitor, as the antibody typically binds a non-enzymatically active portion of the molecule that leads to accelerated clearance, but characteristically the PT is prolonged and levels of factor II are low. FFP should be administered for treatment of bleeding. Treatment is immunosuppressive.
Products containing bovine factor V (such as topical thrombin or fibrin glue, frequently used in surgical procedures) can lead to formation of an anti-factor V antibody that has specificity for human factor V. Clinicopathologic manifestations range from a prolonged PT in an otherwise asymptomatic individual to severe bleeding. Mixing studies suggest the presence of an inhibitor, and the factor V activity level is low. In cases of serious or life-threatening bleeding, IVIG or platelet transfusions, or both, should be administered, and immunosuppression (as for acquired inhibitors to factor VIII) may be offered.
Vitamin K deficiency may occur as a result of deficient dietary intake of vitamin K (from green leafy vegetables, soybeans, and other sources), malabsorption, or decreased production by intestinal bacteria (due to treatment with chemotherapy or antibiotics). Vitamin K normally participates in activity of the vitamin K epoxide reductase that assists in posttranslational gamma-carboxylation of the coagulation factors II, VII, IX, and X that is necessary for their activity. Thus, vitamin K deficiency typically features a prolonged PT (in which the activity of the vitamin K–dependent factors is more reflected than in the aPTT) that corrects upon mixing; levels of individual clotting factors II, VII, IX, and X typically are low. Importantly, a concomitantly low factor V activity level is not indicative of isolated vitamin K deficiency, and may indicate an underlying defect in liver synthetic function (see below).
For treatment, vitamin K1 (phytonadione) may be administered via intravenous or oral routes; the subcutaneous route is not recommended due to erratic absorption. The oral dose is 5–10 mg/d and absorption is typically excellent; at least partial improvement in the PT should be observed within 1 day of administration. Intravenous administration (1 mg/d) results in even faster normalization of a prolonged PT than oral administration; due to descriptions of anaphylaxis, parenteral doses should be administered at lower doses and slowly (eg, over 30 minutes) with concomitant monitoring.
Impaired hepatic function due to cirrhosis or other causes leads to decreased synthesis of clotting factors, including factors II, VII, V, IX, and fibrinogen, whereas factor VIII levels may be elevated in spite of depressed levels of other coagulation factors. The PT (and with advanced disease, the aPTT) is typically prolonged and corrects on mixing with normal plasma. A normal factor V level, in spite of decreases in the activity of factors II, VII, IX, and X, however, suggests vitamin K deficiency rather than liver disease (see above). Qualitative and quantitative deficiencies of fibrinogen also are prevalent among patients with advanced liver disease, typically leading to a prolonged PT, thrombin time, and reptilase time.
The coagulopathy of liver disease usually does not require hemostatic treatment until bleeding complications occur. Infusion of FFP may be considered if active bleeding is present and the aPTT and PT are markedly prolonged; however, the effect is transient and concern for volume overload may limit infusions. Patients with bleeding and a fibrinogen level consistently below 80 mg/dL should receive cryoprecipitate. Liver transplantation, if feasible, results in production of coagulation factors at normal levels. The appropriateness of use of recombinant human activated factor VII in patients with bleeding varices is controversial, although some patient subgroups may experience benefit.
Franchini M et al. Acquired factor V inhibitors: a systematic review. J Thromb Thrombolysis. 2011 May;31(4):449–57. [PMID: 21052780]
Pluta A et al. Coagulopathy in liver diseases. Adv Med Sci. 2010 Jun;55(1):16–21. [PMID: 20513645]
See Antithrombotic Therapy section, below.
The consumptive coagulopathy of DIC results in decreases in the activity of clotting factors, leading to bleeding in most patients (see above). The aPTT and PT are characteristically prolonged, and platelets and fibrinogen levels are reduced from baseline.
The thrombin time is dramatically prolonged in the presence of heparin. Patients who are receiving heparin and who have bleeding should be managed by discontinuation of the heparin and (some cases) administration of protamine sulfate; 1 mg of protamine neutralizes approximately 100 units of heparin sulfate, and the maximum dose is 50 mg intravenously. LMWHs typically do not prolong clotting times and are incompletely reversible with protamine. There is no reversal agent for fondaparinux, although some experts have suggested using recombinant human activated factor VIIa for cases of life-threatening bleeding. The novel oral anticoagulants include rivaroxaban and dabigatran, and have no specific antidote.
Eerenberg ES et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011 Oct 4;124(14):1573–9. [PMID: 21900088]
Siegal DM et al. Acute management of bleeding in patients on novel oral anticoagulants. Eur Heart J. 2013 Feb;34(7):489–498b. [PMID: 23220847]
Lupus anticoagulants do not cause bleeding; however, because they prolong clotting times by binding proteins associated with phospholipid, which is a necessary component of coagulation reactions, clinicians may be concerned about a risk of bleeding. Lupus anticoagulants were so named because of their increased prevalence among patients with connective tissue disease, although they may occur with increased frequency in individuals with underlying infection, inflammation, or malignancy, and they also can occur in asymptomatic individuals in the general population. A prolongation in the aPTT is observed that does not correct completely on mixing. Specialized testing such as the hexagonal phase phospholipid neutralization assay, the dilute Russell viper venom time, and platelet neutralization assays can confirm the presence of a lupus anticoagulant.
Adams M. Measurement of lupus anticoagulants: an update on quality in laboratory testing. Semin Thromb Hemost. 2013 Apr;39(3):267–71. [PMID: 23424052]
OTHER CAUSES OF BLEEDING
Occasionally, abnormalities of the vasculature and integument may lead to bleeding despite normal hemostasis; congenital or acquired disorders may be causative. These abnormalities include Ehlers-Danlos syndrome, osteogenesis imperfecta, Osler-Weber-Rendu disease, and Marfan syndrome (heritable defects) and integumentary thinning due to prolonged corticosteroid administration or normal aging, amyloidosis, vasculitis, and scurvy (acquired defects). The bleeding time often is prolonged. If possible, treatment of the underlying condition should be pursued, but if this is not possible or feasible (ie, congenital syndromes), globally hemostatic agents such as DDAVP can be considered for treatment of bleeding. Topical bevacizumab has been effective in some patients with refractory nosebleeds.
Karnezis TT et al. Treatment of hereditary hemorrhagic telangiectasia with submucosal and topical bevacizumab therapy. Laryngoscope. 2012 Mar;122(3):495–7. [PMID: 22147664]
McDonald J et al. Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis. Genet Med. 2011 Jul;13(7):607–16. [PMID: 21546842]
Prevention of Venous Thromboembolic Disease
The frequency of venous thromboembolic disease (VTE) among hospitalized patients ranges widely; up to 20% of medical patients and 80% of critical care patients and high-risk surgical patients have been reported to experience this complication, which includes deep venous thrombosis (DVT) and pulmonary embolism (PE).
Avoidance of fatal PE, which occurs in up to 5% of high-risk inpatients as a consequence of hospitalization or surgery is a major goal of pharmacologic prophylaxis. Tables 14–11 and 14–12 provide risk stratification for DVT/VTE among hospitalized surgical and medical inpatients. Standard prophylactic regimens are listed in Table 14–13. Prophylactic strategies should be guided by individual risk stratification, with all moderate- and high-risk patients receiving pharmacologic prophylaxis, unless contraindicated. Contraindications to VTE prophylaxis for hospital inpatients at high risk for VTE are listed in Table 14–14.
Table 14–11. Risk stratification for DVT/VTE among surgical inpatients.
Table 14–12. Padua Risk Assessment Model for VTE prophylaxis in hospitalized medical patients.
Table 14–13. Pharmacologic prophylaxis of VTE in selected clinical scenarios.1
Table 14–14. Contraindications to VTE prophylaxis for medical or surgical hospital inpatients at high risk for VTE.
It is recommended that VTE prophylaxis be used judiciously in hospitalized medical patients who are not critically ill since a comprehensive review of evidence suggested harm from bleeding in low-risk patients given low-dose heparin and skin necrosis in stroke patients given compression stockings. The Padua Risk Score provides clinicians with a simple validated approach to risk stratification in medical patients (Table 14–12). Certain high-risk surgical patients should be considered for extended-duration prophylaxis, of approximately 1 month, including those undergoing total hip replacement, hip fracture repair, and abdominal and pelvic cancer surgery. If bleeding is present, if the risk of bleeding is high, or if the risk of VTE is high for the inpatient (Table 14–11) and therefore combined prophylactic strategies are needed, some measure of thromboprophylaxis may be provided through use of mechanical devices, including intermittent pneumatic compression devices, venous foot pumps, or graduated compression stockings.
Barbar S et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost. 2010 Nov;8(11):2450–7. [PMID: 20738765]
Falck-Ytter Y et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e278S–325S. [PMID: 22315265]
Gould MK et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e227S–77S. Erratum in: Chest. 2012 May;141(5):1369. [PMID: 22315263]
Kahn SR et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e195S–226S. [PMID: 2231526]
Neumann I et al. Oral direct Factor Xa inhibitors versus low-molecular-weight heparin to prevent venous thromboembolism in patients undergoing total hip or knee replacement: a systematic review and meta-analysis. Ann Intern Med. 2012 May 15;156(10):710–9. [PMID: 22412038]
Qaseem A et al. Venous thromboembolism prophylaxis in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2011 Nov 1;155(9):625–32. [PMID: 22041951]
Treatment of Venous Thromboembolic Disease
Treatment for VTE should be offered to patients with objectively confirmed DVT or PE, or to those in whom the clinical suspicion is high for the disorder yet have not yet undergone diagnostic testing (seeChapter 9). The management of VTE primarily involves administration of anticoagulants; the goal is to prevent recurrence, extension and embolization of thrombosis and to reduce the risk of post-thrombotic syndrome. Suggested anticoagulation regimens are found in Table 14–15.
Table 14–15. Initial anticoagulation for VTE.1
Most patients with DVT alone may be treated as outpatients, provided that their risk of bleeding is low, and they have good follow-up. Table 14–16 outlines the selection criteria for outpatient treatment of DVT.
Table 14–16. Patient selection for outpatient treatment of DVT.
Among patients with PE, risk stratification should be done at time of diagnosis to direct treatment and triage. Patients with persistent hemodynamic instability (or patients with massive PE) are classified as high risk and have an early PE-related mortality of > 15%. These patients should be admitted to an intensive care unit and receive thrombolysis in addition to anticoagulation. Intermediate-risk patients have a mortality rate of up to 15% and should be admitted to a higher level of inpatient care, with consideration of thrombolysis on a case-by-case basis. Those classified as low risk have a mortality rate < 3% and are candidates for expedited discharge or outpatient therapy.
Because both intermediate- and low-risk patients are hemodynamically stable, additional assessment is necessary to differentiate the two. Echocardiography can be used to identify patients with right ventricular dysfunction, which connotes intermediate risk. However, real-time echocardiography involves added cost and is not always immediately available. An RV/LV ratio < 1.0 on chest CT angiogram has been shown to have good negative predictive value for adverse outcome but suffers from inter-observer variability. Serum biomarkers such as B-type natriuretic peptide and troponin have been studied and are most useful for their negative predictive value, and mainly in combination with other predictors. The PESI (pulmonary embolism severity index) clinical risk score, which does not require additional testing, has been validated and accurately identifies patients at low risk for 30-day PE-related mortality A simplified version of this risk score has been validated as well (Table 14–17).
Table 14–17. Simplified Pulmonary Embolism Severity Index (PESI).
Weight-based, fixed-dose daily subcutaneous fondaparinux (a synthetic factor Xa inhibitor) may also be used for the initial treatment of DVT and PE, with no increase in bleeding over that observed with LMWH. Its lack of reversibility, long half-life, and primarily renal clearance limits its use in patients with an increased risk of bleeding or renal failure.
Table 14–18. Warfarin adjustment guidelines for patients newly starting therapy.
Table 14–19. Warfarin-dosing adjustment guidelines for patients receiving long-term therapy.
Table 14–20. American College of Chest Physicians Evidence-based Clinical Practice Guidelines for the Management of Nontherapeutic INR.
Table 14–21. Duration of treatment of VTE.
Table 14–22. Candidates for thrombophilia work-up if results will influence management.
Table 14–23. Laboratory evaluation of thrombophilia.
Compared with placebo, aspirin has been shown to reduce risk of recurrent VTE by 30% in patients with idiopathic VTE. Low-dose aspirin therapy should be considered in patients with unprovoked VTE who are not candidates for ongoing anticoagulation.
Agnelli G et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799–808. [PMID: 23808982]
Aujesky D et al. Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial. Lancet. 2011 Jul 2;378(9785):41–8. [PMID: 21703676]
Brighton TA et al; ASPIRE Investigators. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012 Nov 22;367(21):1979–87. [PMID: 23121403]
EINSTEIN–PE Investigators;Büller HR et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287–97. [PMID: 22449293]
Erkens PM et al. Does the Pulmonary Embolism Severity Index accurately identify low risk patients eligible for outpatient treatment? Thromb Res. 2012 Jun;129(6):710–4. [PMID: 21906787]
Heidbuchel H et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013 May;15(5):625–51. [PMID: 23625942]
Jiménez D et al. Simplification of the Pulmonary Embolism Severity Index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med. 2010;170(15):1383–9. [PMID: 20696966]
Kaatz S et al. Reversal of target-specific oral anticoagulants. J Thromb Thrombolysis. 2013 Aug;36(2):195–202. [PMID: 23657589]
Kearon C et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e419S–94S. [PMID: 22315268]
Kyrle PA et al. Clinical scores to predict recurrence risk of venous thromboembolism. Thromb Haemost. 2012 Dec;108(6):1061–4. [PMID: 22872143]
Scherz N et al. Prospective, multicenter validation of prediction scores for major bleeding in elderly patients with venous thromboembolism. J Thromb Haemost. 2013 Mar;11(3):435–43. [PMID: 23279158]
Schulman S et al; RECOVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342–52. [PMID: 19966341]
Van Spall HG et al. Variation in warfarin dose adjustment practice is responsible for differences in the quality of anticoagulation control between centers and countries: an analysis of patients receiving warfarin in the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial. Circulation. 2012 Nov 6;126(19):2309–16. [PMID: 23027801]
Anticoagulation alone is appropriate treatment for most patients with PE; however, those with high-risk, massive PE, defined as PE with persistent hemodynamic instability, have an in-hospital mortality rate that approaches 30% and require immediate thrombolysis in combination with anticoagulation (Table 14–24). A 50% reduced dosing regimen for tissue plasminogen activator (TPA) has been proposed, offering similar efficacy with lower risk of complications. Thrombolytic therapy also has been used in selected patients with intermediate-risk, submassive PE, defined as PE without hemodynamic instability but with evidence of right ventricular compromise. This approach remains controversial, however, given the paucity of data showing a clinically significant benefit of thrombolysis.
Table 14–24. Thrombolytic therapies for acute massive pulmonary embolism.
Limited data suggest that patients with large proximal iliofemoral DVT may also benefit from catheter-directed thrombolysis in addition to treatment with anticoagulation. However, standardized guidelines are lacking, and use of the intervention may be limited by institutional availability and provider experience. Importantly, thrombolytics should be considered only in patients who have a low risk of bleeding, as rates of bleeding are increased in patients who receive these products compared with rates of hemorrhage in those who are treated with anticoagulation alone.
Enden T et al. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet. 2012 Jan 7;379(9810):31–8. [PMID: 22172244]
Howard LS. Thrombolytic therapy for submassive pulmonary embolus? PRO viewpoint. Thorax. 2014 Feb;69(2):103–5. [PMID: 23624534]
Jaff MR et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011 Apr 26;123(16):1788–830. Erratum in: Circulation. 2012 Aug 14;126(7):e104. Circulation. 2012 Mar 20;125(11):e495. [PMID: 21422387]
Kearon C et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guideline (8th Edition). Chest. 2008 Jun;133(6 Suppl):454S–545S. [PMID: 18574272]
Simpson AJ. Thrombolysis for acute submassive pulmonary embolism: CON viewpoint. Thorax. 2014 Feb;69(2):105–7. [PMID: 24046127]
Wang C et al; China Venous Thromboembolism (VTE) Study Group. Efficacy and safety of low dose recombinant tissue-type plasminogen activator for the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial. Chest. 2010 Feb;137(2):254–62. [PMID: 19741062]
Complications of IVC filters include local thrombosis, tilting, migration, fracture, and inability to retrieve the device. When considering placement of an IVC filter, it is best to consider both short- and long-term complications, since devices intended for removal may becomepermanent. To improve patient safety, institutions should develop systems that guide appropriate patient selection for IVC filter placement, tracking, and removal.
PREPIC Study Group. Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prévention du Risque d’Embolie Pulmonaire par Interruption Cave) randomized study. Circulation. 2005 Jul 19;112(3):416–22. [PMID: 16009794]
Sarosiek S et al. Indications, complications, and management of inferior vena cava filters: the experience in 952 patients at an academic hospital with a level I trauma center. JAMA Intern Med. 2013 Apr 8;173(7):513–7. [PMID: 23552968]
When to Refer
When to Admit