Tzu-Fei Wang, Charles S. Eby, and Ronald Jackups Jr.
GENERAL PRINCIPLES
· Normal hemostasis involves a complex sequence of interrelated reactions that lead to platelet aggregation (primary hemostasis) and activation of coagulation factors (secondary hemostasis) to produce a durable vascular seal.
· Primary hemostasis is an immediate but temporary response to vessel injury. Platelets and von Willebrand factor (vWF) interact to form a primary plug.
· Secondary hemostasis (coagulation) results in the formation of a fibrin clot (Fig. 12-1). Injury initiates coagulation by exposing extravascular tissue factor to blood, which initiates activation of factors VII, X, and prothrombin. The subsequent activation of other factors leads to the generation of thrombin, conversion of fibrinogen to fibrin, and formation of a durable clot.1
Figure 12-1 Coagulation cascade. Solid arrows indicate activation and dashed lines indicate additional substrates activated by factor VIIa or thrombin. aPTT, activated partial thromboplastin time; HMWK, high molecular weight kininogen; PL phospholipid; PT, prothrombin time; TF, tissue factor.
DIAGNOSIS
Clinical Presentation
History
· A detailed history can assess bleeding severity, congenital or acquired status, and primary or secondary hemostatic defects.
· Prolonged bleeding after dental extractions, circumcision, menstruation, labor and delivery, trauma, or surgery may suggest an underlying bleeding disorder.
· Strong family history may suggest an inherited bleeding disorder.
Physical Examination
· Primary hemostasis defects are suggested by mucosal bleeding and excessive bruising.
o Petechiae: <2-mm foci of subcutaneous bleeding that do not blanch with pressure and typically present in areas subject to increased hydrostatic force: the lower legs and periorbital area (especially after coughing or vomiting)
o Ecchymoses: >3-mm black-and-blue (or violaceous) patches due to rupture of small vessels from trauma
· Secondary hemostasis defects can produce hematomas (localized masses of clotted/unclotted blood), hemarthroses, or delayed bleeding after trauma or surgery.
Diagnostic Testing
Laboratories
The history and physical exam guide test selection: Initial studies should include platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), and peripheral blood smear.
Primary Hemostasis Testing
· A low platelet count requires a review of a blood smear to rule out platelet clumping artifact (often due to the EDTA additive), giant platelets, and misclassification of other cells as platelets.
· The bleeding time (BT) measures time until bleeding cessation from a standardized skin incision, but it does not quantify the perioperative risk of bleeding.2 While the BT is used to detect qualitative platelet defects, it is considered a poor test due to low accuracy and high interoperator variability. The platelet function analysis (PFA)-100 now replaces BT in most laboratories.
· The PFA-100 instrument assesses vWF-dependent platelet activation in flowing citrated whole blood. Most patients with von Willebrand disease (vWD) and qualitative platelet disorders have prolonged closure times. Anemia (hematocrit <30%) and thrombocytopenia (platelet count of <100 × 109/L) can cause artifactually prolonged closure times.
· In vitro platelet aggregation studies measure platelet secretion and aggregation in response to platelet agonists (e.g., adenosine diphosphate [ADP], collagen, arachidonic acid, and epinephrine), and they assist with the diagnosis of qualitative platelet disorders.
· Laboratory evaluation of vWD is discussed later in this chapter.
Secondary Hemostasis Testing
· Prothrombin time (PT): Measures time to form a fibrin clot after adding thromboplastin (tissue factor and phospholipid) and calcium to citrated plasma.
o Sensitive to deficiencies of the extrinsic pathway (factor VII), common pathway (factors X and V and prothrombin), and fibrinogen.
o Sensitive to anticoagulation therapy with warfarin and may also be prolonged with the use of direct thrombin inhibitors (DTIs) and factor Xa inhibitors.
o Reporting a PT ratio as an international normalized ratio (INR) reduces interlaboratory variation for monitoring warfarin therapy.3
· Activated partial thromboplastin time (aPTT): Measures the time to form a fibrin clot after activation of citrated plasma by calcium, phospholipid, and negatively charged particles.
o Sensitive to deficiencies of the intrinsic pathway (factors VIII, IX, and XI), common pathway, and fibrinogen and to clinically insignificant deficiencies of the contact activators (factor XII, prekallikrein, and high molecular weight kininogen).
o Sensitive to anticoagulation therapy with unfractionated heparin and may also be prolonged with use of direct thrombin inhibitors (DTIs) and factor Xa inhibitors.
o Although the aPTT may be prolonged with use of low molecular weight heparin (enoxaparin), monitoring of therapeutic anticoagulation should be performed with the anti–factor Xa inhibitor assay.
· Thrombin time: Measures time to form a fibrin clot after addition of thrombin to citrated plasma. Quantitative and qualitative deficiencies of fibrinogen, elevated fibrin degradation products, heparin, and DTIs may prolong the thrombin time.
· Fibrinogen: The addition of thrombin to dilute plasma and the measurement of a clotting time determine the effective functional concentration of fibrinogen. Conditions causing hypofibrinogenemia include decreased hepatic synthesis, massive hemorrhage, and disseminated intravascular coagulation (DIC).
· D-dimers result from plasmin digestion of fibrin. Elevated D-dimer concentrations occur in many disease states, including acute venous thromboembolism, DIC, trauma, and malignancy.
· General workup of unexpected prolonged PT or aPTT should include the following:
o Consideration of preanalytic variables such as incomplete filling of sample tubes, heparin contamination (screen with thrombin time), high hematocrit (>55%), hemolysis, and lipemia.
o A mixing study (performing PT or aPTT on the patient’s plasma mixed 1:1 with normal pooled plasma) will differentiate factor deficiencies from inhibitors:
§ Correction of PT or aPTT to within reference range after mixing: simple deficiency of factor(s), depending on whether PT and/or aPTT is prolonged. Hemophilias, acquired deficiencies, and warfarin result in this pattern.
§ No or minimal correction: factor inhibitor, depending on whether PT and/or aPTT are prolonged. Autoantibodies and alloantibodies to factors result in this pattern, as do heparins, DTIs, and lupus anticoagulants.
o Common causes of PT and aPTT prolongation (Table 12-1):
§ PT and aPTT prolonged: hypofibrinogenemia, common pathway factor (II, V, X) deficiencies, DIC, liver disease, dilutional coagulopathy, DTIs, factor Xa inhibitors, and superwarfarin (e.g., brodifacoum) toxicity
§ PT only: warfarin, vitamin K deficiency, liver disease, factor VII deficiency
§ aPTT only: Heparin, common hemophilias (factor VIII, IX, or XI deficiency)
§ Most common inhibitors that prolong the aPTT are factor VIII inhibitors (if bleeding is present) and lupus anticoagulants (if there is no history of bleeding)
TABLE 12-1 Factor Deficiencies Causing Prolonged Prothrombin Time (PT) and/or Activated Partial Thromboplastin Time (aPTT) That Correct with 50:50 Mix
PLATELET DISORDERS
Quantitative Platelet Disorders (Thrombocytopenia)
· Thrombocytopenia is defined as a platelet count of <140 to 150 × 109/L at most laboratories. In the absence of qualitative platelet defects or vascular damage, spontaneous bleeding often does not occur until the platelet count is <10 to 30 × 109/L.
· Thrombocytopenia occurs from decreased production, increased destruction, or sequestration of platelets (Table 12-2). Many infectious diseases are associated with thrombocytopenia through complex or poorly understood mechanisms.4
TABLE 12-2 Classification of Thrombocytopenia
DIC, disseminated intravascular coagulation; HELLP, Hemolysis (with microangiopathy), Elevated Liver enzymes, and Low Platelet count; HUS, hemolytic uremic syndrome.
Immune Thrombocytopenic Purpura
GENERAL PRINCIPLES
Immune thrombocytopenic purpura (ITP) is an acquired autoimmune disorder in which antiplatelet antibodies cause shortened platelet survival and suppress megakaryopoiesis, leading to thrombocytopenia and increased bleeding risk. ITP can be classified into primary (idiopathic) and secondary (associated with coexisting conditions, including systemic lupus erythematosus, antiphospholipid antibody syndrome, HIV, hepatitis C, Helicobacter pylori, and lymphoproliferative disorders).4
DIAGNOSIS
Clinical Presentation
· ITP typically presents as mild mucocutaneous bleeding and petechiae or thrombocytopenia discovered incidentally.
· Primary ITP often has the scenario of isolated thrombocytopenia in the absence of a likely underlying causative disease or medication.
Diagnostic Testing
· Laboratory tests do not confirm the presence of primary ITP, though they help to exclude some secondary causes.
· Serologic tests for antiplatelet antibodies do not help diagnose ITP because of poor sensitivity and low negative predictive value and should not be used routinely.5
· Bone marrow biopsy and aspirate studies are not necessary in patients with typical presentations of ITP, irrespective of age. However, if patients have other abnormalities identified in history, physical examination, or peripheral blood count, bone marrow biopsy may be needed to exclude other causes such as malignancy, especially in older patients (age >60 years) and patients who do not respond to standard ITP treatments.6
· All newly diagnosed adult ITP patients should be tested for HIV and HCV.
TREATMENT
· The decision to treat primary ITP depends upon the severity of thrombocytopenia and symptoms of bleeding.
· Management of secondary ITP includes treatment of the underlying disease and standard primary ITP therapy.
· Initial therapy, when indicated, consists of glucocorticoids (typically prednisone 1 mg/kg/day for 2 to 3 weeks then taper depending on the patient’s responses and stability of platelet count).
· Steroid nonresponders or patients with active bleeding often also receive intravenous immunoglobulin (IVIG) (1 g/kg × 2 days) or anti–D immunoglobulin (WinRho) if Rh positive. Anti–D immunoglobulin is ineffective postsplenectomy.
· Approximately 80% of patients will respond to glucocorticoids initially with resolution of thrombocytopenia within 1 to 3 weeks.
· Steroid nonresponders and the 30% to 40% of patients who relapse during a steroid taper have chronic ITP. The therapeutic goals in refractory and relapsed ITP patients include a safe platelet count (>30 × 109/L) and minimization of treatment-related toxicities.
· Treatment options for refractory or relapsed ITP: The optimal sequence or choice of the following three treatment options has not been established and is usually determined by patient preference/conditions.
o Splenectomy: Two-thirds of patients with refractory ITP will obtain a durable complete response following splenectomy. Administer pneumococcal, meningococcal, and Haemophilus influenzae type B vaccines at least 2 weeks before splenectomy.
o Rituximab, an anti-CD20 monoclonal antibody, or much less commonly, other immunosuppressive agents such as cyclosporine, azathioprine, or androgen therapy with danazol.6,7
o Thrombopoietin (TPO) receptor agonists:
§ Two small-molecule TPO receptor agonists are available for refractory ITP patients with increased bleeding risk. Romiplostim is given subcutaneously once weekly and eltrombopag orally once a day.
§ Both produce durable platelet count improvements in 80% to 90% of refractory ITP patients after 5 to 7 days.
§ Potential complications include transaminitis, thromboembolic events, and bone marrow fibrosis.8
Drug-Induced Thrombocytopenia
GENERAL PRINCIPLES
Drug-dependent immune thrombocytopenia results from drug-platelet interactions prompting antibody binding.9 Medications that are commonly associated with thrombocytopenia are listed in Table 12-3.10An extensive list of medications with references can be found on the website of the University of Oklahoma Health Sciences (http://www.ouhsc.edu/platelets/DITP.html, last accessed January 2, 2015).
TABLE 12-3 Drugs Implicated in Immune Thrombocytopenia
DIAGNOSIS
Key factors to diagnose drug-induced thrombocytopenia:
· Exposure of suspected drug(s) precede(s) thrombocytopenia.
· Normalization of platelet counts with discontinuation of suspected drug(s).
· No other likely drugs present.
· No other more likely etiologies for thrombocytopenia.
· Thrombocytopenia recurs when patients are rechallenged with the same drug.
TREATMENT
· Discontinuation of the suspected offending agent(s) is the main therapy.
· Platelet transfusion for severe thrombocytopenia may decrease the risk of bleeding, but is discouraged for less severe thrombocytopenia without bleeding. IVIG, steroids, and plasmapheresis have uncertain benefits.
Thrombotic Thrombocytopenic Purpura
GENERAL PRINCIPLES
· The pathogenesis of thrombotic thrombocytopenic purpura (TTP) is the formation of disseminated platelet thrombi. Deficiency of the vWF-cleaving metalloprotease ADAMTS13 (most commonly autoantibody mediated) leads to elevated levels of abnormally large vWF multimers that spontaneously adhere to platelets and form occlusive vWF-platelet aggregates in the microcirculation and subsequent thrombotic microangiopathy (TMA).11Thrombocytopenia due to platelet consumption, microangiopathic hemolytic anemia (MAHA) due to platelet microthrombi, and organ ischemia are characteristic features.
· Sporadic (primary) TTP has an incidence of approximately 11.3 cases per 106 people and occurs more frequently in women and African Americans.12
· Secondary TTP refers to TMA associated with DIC, HIV, malignant hypertension, vasculitis, organ and stem cell transplant–related toxicity, adverse drug reactions, and, during pregnancy, preeclampsia/eclampsia and HELLP (Hemolytic anemia, Elevated Liver enzymes, Low Platelet count) syndrome.
· TMA may also be associated with certain drugs, including quinine, ticlopidine, calcineurin inhibitors (cyclosporine, tacrolimus), sirolimus, and chemotherapy agents such as gemcitabine and mitomycin C.
DIAGNOSIS
Clinical Presentation
· The classic pentad of TTP includes consumptive thrombocytopenia, MAHA, fever, renal dysfunction, and fluctuating neurologic deficits, but is only fully present in <30% of cases. The findings of thrombocytopenia and MAHA alone should raise suspicion for TTP.
· Patients with autosomal recessive inherited ADAMTS13 deficiencies have recurrent TTP (Upshaw-Schulman syndrome).
Diagnostic Testing
· Schistocytes and thrombocytopenia on peripheral blood smears are classical findings.
· Hemolysis workup is often positive including anemia, elevated reticulocyte count, low haptoglobin, elevated lactate dehydrogenase, and elevated indirect bilirubin.
· TTP is often associated with very low or undetectable ADAMTS13 enzyme activity and an ADAMTS13 inhibitory antibody. However, TREATMENT should not be delayed for such testing, due to the urgency of the disease.
Treatment
· The mainstay of therapy is plasma exchange (PEX), requiring emergent inpatient admission Glucocorticoids (prednisone 1 mg/kg/day orally or methylprednisolone 1 g IV daily) are commonly initiated along with PEX. Treatment for refractory or relapsed TTP may include rituximab, cyclosporine, or vincristine.13–16
· Platelet transfusion in the absence of severe bleeding is relatively contraindicated because of the potential risk of additional microvascular occlusions.
· When TMA is suspected to be due to drugs, discontinuation of the offending agent is the preferred therapy. PEX is usually not effective.
Hemolytic-Uremic Syndrome
GENERAL PRINCIPLES
· The clinical pentad of TTP can also be found in hemolytic-uremic syndrome (HUS), but HUS is usually associated with higher incidence of renal dysfunction and lower incidence of neurologic manifestations.
· There are two types of HUS, typical and atypical.
o Typical HUS (diarrhea associated) often follows acute infection with Escherichia coli (especially serotype O157:H7) or Shigella dysenteriae that produce Shiga-like toxins.
o Atypical HUS (aHUS) has the clinical presentation of HUS without being preceded by the above-mentioned infections or diarrhea. Acquired and inherited defects in regulation of the alternative pathway of complement activation are frequently identified.17
DIAGNOSIS
Clinical Presentation
· Diarrhea (often bloody) and abdominal pain often precede typical HUS, and more pronounced renal dysfunction occurs.
· Familial atypical HUS often leads to chronic renal failure.
Diagnostic Testing
· Features of TMA and acute renal failure are usually present.
· In typical HUS, stool culture for E. coli O157 has a higher sensitivity than Shiga toxin assays.18
· ADAMTS13 activity is often normal or only mildly decreased (in contrast to TTP, which is associated with a very low ADAMTS13 activity).
· Workup for suspected aHUS should include molecular analysis of complement regulator factor H and I and MCP (membrane cofactor protein) genes as well as analysis for acquired inhibitors through reference laboratories.
TREATMENT
· Inpatient admission is recommended based on the severity of the presentation.
· Typical HUS:
o Treatment is supportive care (e.g., hydration).
o Antibiotics do not hasten recovery or minimize toxicity for HUS-associated infection.
o PEX is not recommended due to a demonstrated lack of benefit.
· Atypical HUS:
o PEX can provide some benefit, but is often less effective than for TTP.
o Eculizumab, a monoclonal antibody against the complement protein C5, inhibits the complement-mediated renal injury.
Heparin-Induced Thrombocytopenia
GENERAL PRINCIPLES
· Heparin-induced thrombocytopenia (HIT) is an acquired hypercoagulable disorder caused by antibodies targeting heparin and platelet factor 4 (PF4) complexes, which can activate platelets, cause thrombocytopenia, and increase thrombin generation.19
· HIT typically presents with a decreased platelet count by at least 50% after exposure to unfractionated heparin (UFH) or (less likely) low molecular weight heparin (LMWH).
· The incidence of HIT varies with clinical setting, anticoagulant formulation, dose, duration of exposure, and previous exposure, ranging from 0.1% to 1% in medical and obstetric patients receiving prophylactic and therapeutic UFH to 1% to 5% in patients receiving prophylactic UFH after total hip or knee replacements or cardiothoracic surgery.20
DIAGNOSIS
Clinical Presentation
· Suspect HIT when thrombocytopenia occurs during heparin exposure by any route in the absence of other causes of thrombocytopenia and when platelet counts recover after cessation of heparin.
· HIT usually develops between 5 and 14 days of heparin exposure (typical-onset HIT). Exceptions include delayed-onset HIT, which occurs after stopping heparin, and early-onset HIT, which starts within the first 24 hours of heparin administration in patients with recent exposure to heparin.20
· Both venous and arterial thromboembolic complications occur due to activation of platelets. Thrombosis can precede, be concurrent with, or follow recognition of thrombocytopenia. Thrombi may occur at heparin injection sites as full-thickness skin infarctions, sometimes in the absence of thrombocytopenia. HIT rarely causes severe thrombocytopenia (<20 × 109/L) and bleeding.
Diagnostic Testing
· A scoring system based on the “4Ts” improves diagnostic accuracy: thrombocytopenia, timing, thrombosis, and other explanations for thrombocytopenia (Table 12-4).21 A 4 T score of 3 or below correlates with a low probability of HIT and high negative predictive value (0.998).22 A HIT assay should NOT be ordered due to the high false-positive rate in this population.
· There are two main types of HIT assays:
o Serologic enzyme immunoassays (PF4 EIA) to detect heparin-PF4 antibodies
o Functional assays: platelet aggregometry or serotonin release assay to detect activation of control platelets in the presence of patient serum and heparin
· In comparison, serologic tests have higher sensitivity and serve as screening tests, whereas functional assays have higher specificity and may serve as confirmatory tests when the diagnosis is unclear.
TABLE 12-4 The 4Ts Scoring System23
PLT, platelet.
TREATMENT
· When HIT is strongly suspected, begin treatment by eliminating all heparin exposure. Patients with thrombosis and those at high risk for thrombosis require alternative anticoagulation with a parenteral DTI, such as bivalirudin or argatroban (see Chapter 14). LMWH may cross-react with HIT antibodies and should not be used. Do not treat with warfarin initially, as it may exacerbate the prothrombic state of HIT via protein C depletion, resulting in skin necrosis or limb gangrene.
· Perform a lower extremity venous compression ultrasound since it often detects deep vein thrombosis in asymptomatic isolated HIT patients, and the presence of thrombosis mandates longer-duration anticoagulation.19
· Start warfarin only after the platelet count normalizes, and overlap with a DTI for 5 days. The recommended duration of anticoagulation therapy for HIT depends on the clinical scenario: For isolated HIT (without thrombosis), at least until the platelet count recovers, some experts advocate anticoagulation for 6 weeks after the normalization of platelet count; for HIT-associated thrombosis, typical thromboembolism therapy duration is recommended (see Chapter 14).
Posttransfusion Purpura
· Posttransfusion purpura (PTP) is a rare acquired autoimmune disorder in which antiplatelet alloantibodies cause shortened survival of transfused platelets and paradoxically of native platelets, leading to severe thrombocytopenia and increased bleeding risk.
· Thrombocytopenic purpura and bleeding typically occur 8 to 10 days after blood transfusion. Due to the delay in presentation, its association to the preceding transfusion event is frequently missed.
· Testing for platelet antibodies may help to confirm the diagnosis, but treatment should not be delayed for testing. The most commonly identified antibody is anti–HPA-1a.
· First-line therapy is IVIG and is usually successful. Plasma exchange may be considered as second-line therapy if IVIG fails. Transfusion of HPA-1a–negative platelets may provide a better response in platelet counts during the thrombocytopenic phase. PTP is self-limiting, but may recur following future transfusions.
Gestational Thrombocytopenia
· Gestational thrombocytopenia is a benign and mild thrombocytopenia and occurs in 5% to 7% of otherwise uncomplicated pregnancies.
· Gestational thrombocytopenia occurs in the third trimester of pregnancy. The mother is asymptomatic, and thrombocytopenia spontaneously resolves after delivery. The fetus remains unaffected.
· Platelet counts should be no <70 × 109/L. Lower platelet counts should prompt consideration of other causes and appropriate workup.
· Other important differential diagnoses of thrombocytopenia during pregnancy include ITP, preeclampsia, eclampsia, HELLP syndrome, TTP, and DIC.
Chemotherapy-Induced Thrombocytopenia
· Thrombocytopenia is a common temporary side effect of myelosuppressive chemotherapy.
· Treatment is supportive transfusion while patients receive chemotherapy.
· To prevent life-threatening hemorrhage, even in asymptomatic patients, prophylactic platelet transfusion is generally given for platelet count <20 × 109/L in the outpatient setting and for platelet count <10 × 109/L in the inpatient setting. Patients with bleeding or in need of procedures may require higher platelet counts (usually >50 × 109/L but can vary depending on the severity of bleeding and the type of procedure).
· Frequently transfused patients may develop platelet refractoriness due to acquired HLA antibodies that rapidly clear transfused platelets. When suspected, a platelet count should be performed 15 to 60 minutes following transfusion to detect a poor platelet response (<20 to 30 × 109/L increment). Confirmation of refractoriness by identification of HLA antibodies may allow for the use of HLA-compatible or HLA-crossmatched platelet transfusions.
Thrombocytopenia Secondary to Liver Disease
Patients with cirrhosis often have thrombocytopenia due to multiple mechanisms:
· Splenic sequestration from splenomegaly
· Immune destruction by autoantibodies
· Bone marrow suppression from viruses (such as hepatitis C), toxins (such as alcohol), or medications (such as ribavirin or interferon)
· Decreased TPO production by the cirrhotic liver
Familial Thrombocytopenia
· Familial thrombocytopenia is uncommon and is often misdiagnosed as ITP.
· Patients usually present with an incidental finding of mild thrombocytopenia (>100 × 109/L) without evidence of bleeding. Giant platelets may also be seen on peripheral smear (macrothrombocytopenia) that may not be counted by automated cell analyzers.
· A positive family history of thrombocytopenia is crucial to avoid misdiagnosis and exposure of patients to unnecessary ITP therapy.
Qualitative Platelet Disorders
GENERAL PRINCIPLES
· Qualitative platelet disorders should be suspected when patients present with mucocutaneous bleeding and excessive bruising in the setting of an adequate platelet count, normal PT and aPTT, and negative screening tests for vWD.
· Most platelet defects produce prolonged PFA-100 closure times. However, a high clinical suspicion of a disorder in a patient with normal test results should lead to in vitro platelet aggregation studies.
· Inherited disorders of platelet function include receptor defects, aberrant signal transduction, cyclooxygenase defects, secretory (e.g., storage pool disease) defects, and adhesion or aggregation defects. In vitro platelet aggregation studies can identify patterns of agonist responses consistent with a particular defect such as the rare autosomal recessive disorders of Bernard-Soulier syndrome (defect of platelet glycoprotein Ib/IX/V [vWF receptor]) and Glanzmann thrombasthenia (defect of glycoprotein IIb/IIIa [fibrinogen receptor]).
· Acquired platelet defects occur much more commonly than do hereditary platelet qualitative disorders.
o Conditions associated with acquired qualitative defects include myeloproliferative diseases, myelodysplasia, acute leukemia, monoclonal gammopathy, metabolic disorders (e.g., uremia, liver failure), and exposure to cardiopulmonary bypass trauma.
o Drug-induced platelet dysfunction occurs as a side effect of many drugs that include high-dose penicillin, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and alcohol. Other drug classes, such as β-lactam antibiotics, β-blockers, calcium channel blockers, nitrates, antihistamines, psychotropic drugs, tricyclic antidepressants, and selective serotonin reuptake inhibitors, cause platelet dysfunction in vitro but rarely cause bleeding.
§ Aspirin irreversibly inhibits cyclooxygenase (COX)-1 and COX-2. Its effects can last for 7 to 10 days from last consumption of the medication.
§ Since other NSAIDs reversibly inhibit COX-1 and COX-2, their effects are shorter than aspirin. COX-2 inhibitors have minimal effects on platelets at therapeutic doses.
§ Thienopyridines (e.g., clopidogrel, prasugrel, ticlopidine) inhibit platelet aggregation by irreversibly blocking platelet ADP receptor P2Y12.
§ Dipyridamole, alone or in combination with aspirin, inhibits platelet function by increasing intracellular cyclic adenosine monophosphate.
§ Abciximab, eptifibatide, and tirofiban block glycoprotein IIb/IIIa–dependent platelet aggregation during management of acute coronary syndrome.
TREATMENT
· Transfusion of platelets is reserved for major bleeding episodes.
· Treatment of uremic platelet dysfunction includes the following:
o Dialysis to improve uremia.
o Increase of hematocrit to ≥30% by transfusion or erythropoietin.
o Desmopressin (diamino-8-D-arginine vasopressin [DDAVP], 0.3 μg/kg IV) to stimulate release of vWF from endothelial cells.
o Conjugated estrogens (0.6 mg/kg IV daily for 5 days) may improve platelet function for up to 2 weeks.
o Platelet transfusions in actively bleeding patients, though transfused platelets can rapidly acquire the uremic defect.
· Withhold antiplatelet agents for 7 to 10 days before elective invasive procedures.
INHERITED COAGULATION DISORDERS
Hemophilia A
GENERAL PRINCIPLES
· Hemophilia A is an X-linked recessive coagulation disorder due to mutations in the gene encoding factor VIII. It affects approximately 1 in 5,000 live male births.
· Approximately 20% to 30% of cases occur in patients without a family history of hemophilia, reflecting the high rate of spontaneous germ line mutations in the factor VIII gene.23
· Factor VIII activity determines bleeding risk: severe (factor VIII level <1%), moderate (1% to 5%), and mild (5% to 40%).
DIAGNOSIS
Clinical Presentation
· The typical presentation involves patients with a history of recurrent bleeding, prolonged aPTT and normal PT, and possibly a positive family history of bleeding on the maternal side. Nearly all patients are male. Age at diagnosis may differ based on the severity of the disease.
· Patients with mild or moderate hemophilia may present with hemorrhage only when challenged by trauma or invasive procedures (dental extractions, surgery).
· Severe hemophiliacs present with spontaneous joint, muscle, and gastrointestinal (GI) bleeding. Spontaneous hemarthroses are particularly characteristic. Recurrent hemarthroses can lead to hemophilic arthropathy. Intracranial hemorrhage occurs in a few very severely affected patients in the perinatal period.
Diagnostic Testing
· PT and platelet count are normal.
· aPTT is prolonged but may be within the reference range in some mild hemophilics.
· Factor VIII activities are diagnostic (severe hemophilia, <1%; moderate, 1% to 5%; and mild, 5% to 40%).
TREATMENT
· The severity of factor VIII deficiency and the type of hemorrhage or expected surgery/invasive procedures determine intensity of therapy.
· In patients with mild-to-moderate hemophilia A and a minor bleeding episode, DDAVP (0.3 μg/kg IV or 300 μg intranasally dosed every 12 hours) typically increases factor VIII activity three- to fivefold and has a half-life of 8 to 12 hours. Tachyphylaxis typically occurs after several doses.24
· Patients with mild-to-moderate hemophilia A and major bleeding episodes or those with severe hemophilia A with any hemorrhage require factor VIII replacement.
o Many hemophiliacs infuse factor VIII concentrates at home when needed. Recombinant factor VIII concentrates have become the first choice of agent, particularly for children who are initiated on factor VIII.
o Plasma factor VIII activity level increases approximately 2% for every 1 IU/kg of factor VIII concentrate infused. Factor VIII must be dosed q12 hours given its half-life of 8 to 12 hours. The duration and intensity of factor replacement depend on the type of surgery/procedure and the target factor VIII activity. Measure factor VIII activity pre- and postinfusion initially to establish the patient’s response to infusion.
o Factor VIII concentrates dosed to a goal peak plasma activity of 30% to 50% typically stop minor hemorrhages. Major traumas and surgery require maintenance of factor VIII peak activities at >80% for extended periods.
o Patients who have been treated with factor VIII concentrates should be evaluated for factor VIII inhibitors before an elective surgery or invasive procedure is performed (see section below on Complications of Therapy for Hemophilia).
Hemophilia B
· Hemophilia B is an X-linked recessive bleeding disorder secondary to mutations in the gene encoding factor IX. Hemophilia B affects approximately 1 in 30,000 male births.
· Hemophilia B is clinically indistinguishable from hemophilia A, except for deficient factor IX, rather than factor VIII, activities.
· DDAVP cannot increase factor IX levels and is ineffective for hemophilia B patients.
· Postinfusion peak targets, duration of replacement, and monitoring for treatment of hemophilia B–related bleeding episodes are similar to those provided for hemophilia A, with two differences: Plasma factor IX activity increases approximately 1% for every 1 IU/kg factor IX concentrate infused, and factor IX has a longer half-life of 18 to 24 hours, allowing for q24-hour dosing.
Complications of Therapy for Hemophilia
· Alloantibodies to factor VIII and factor IX (i.e., inhibitors) are among the most severe complications in response to factor replacement and can develop in up to 30% and 5% of severe hemophilia A and B patients, respectively. These alloantibodies neutralize infused factor VIII or factor IX and render them ineffective in correcting coagulopathy.
· Determination of the titer of a factor VIII or factor IX inhibitor predicts inhibitor behavior and guides therapy.
· Treatments for hemophiliacs with inhibitors include inpatient management of acute bleeding and eradication of inhibitors.
von Willebrand Disease
GENERAL PRINCIPLES
· vWD is the most common inherited bleeding disorder.
· vWD results from an inherited quantitative or qualitative defect of von Willebrand factor (vWF). Most forms of vWD have an autosomal dominant inheritance with variable penetrance, although autosomal recessive forms (types 2N and 3) exist (Table 12-5).
· vWF circulates as multimers of variable size that facilitate adherence of platelets to injured vessel walls and stabilize factor VIII in plasma.
· Classification recognizes three main types of vWD (Table 12-5):25
o Type 1 vWD, a qualitative deficiency of vWF antigen (vWF:Ag) and activity, accounts for 70% to 80% of cases.
o Type 2 vWD includes four subtypes: 2A, selective loss of large multimers; 2B, loss of large and medium multimers due to increased affinity of vWF for platelet glycoprotein Ib; 2M, decreased platelet adhesion without loss of large multimers; and 2N, decreased binding affinity of vWF for factor VIII.
o Type 3 vWD represents a virtually complete deficiency of vWF.26
TABLE 12-5 Hemostasis Test Patterns in von Willebrand Disease
aPTT, activated partial thromboplastin time; factor VIII:c, procoagulant activity of factor VIII; nl, normal; PFA, platelet function analysis; RIPA, ristocetin-induced platelet aggregation; vWF, von Willebrand factor.
DIAGNOSIS
Clinical Presentation
· The characteristic clinical findings consist of mucocutaneous bleeding (epistaxis, menorrhagia, and GI bleeding) and easy bruising.
· Trauma, surgery, or dental extractions may result in life-threatening bleeding in severely affected individuals.
· Patients with mild vWD phenotypes may remain undiagnosed into adulthood.
Diagnostic Testing
· If personal and family bleeding histories support a reasonable pretest likelihood of an inherited primary hemostasis or bleeding disorder, screening for vWD should begin with measurement of vWF antigen and activity and factor VIII activity (Table 12-5).
o vWF:Ag tests measure plasma concentrations of vWF by immunoassay. A deficiency of vWF:Ag detects type 1 and 3 vWD; low or normal levels may occur with type 2 forms.
o vWF:RCo measures agglutination of normal platelets in the presence of patient plasma and ristocetin cofactor (RCo), which enhances the binding of vWF to glycoprotein Ib. Types 1, 3, 2A, 2B, and 2M can all cause decreased platelet agglutination.
o Factor VIII activity may be reduced due to a quantitative deficiency of vWF (types 1 and 3) or vWF mutations that reduce factor VIII binding to vWF (type 2N).
· Suspect a quantitative vWF defect (type 1) with low vWF:Ag and RCo activity and a RCo/vWF:Ag ratio of >0.7.
· Suspect type 2 vWD when RCo/vWF:Ag activity has a ratio of <0.7. vWF multimer analysis by gel electrophoresis assesses for the presence (type 2M) or absence (types 2A and 2B) of large vWF multimers, and a ristocetin-induced platelet aggregation test (the patient’s plasma and the patient’s platelets incubated with ristocetin) distinguishes types 2A and 2M (attenuated) from type 2B (exaggerated) platelet aggregation responses.
· Type 2N appears clinically identical to mild forms of hemophilia A, except that it is inherited in an autosomal recessive pattern, and the half-life of infused factor VIII concentrates is much shorter.
TREATMENT
· DDVAP:
o Minor bleeding in type 1 vWD usually responds to DDAVP.
o DDAVP can induce variable responses in individual patients. Therefore, test dose administration to confirm clinically acceptable increments of vWF:Ag, vWF:RCo, and factor VIII is needed for all patients.
o vWF:RCo activities of >50% control most hemorrhages.
o DDAVP with or without the oral antifibrinolytic drug aminocaproic acid is recommended for inpatient minor invasive procedures.
o DDAVP does not effectively treat some type 2A, 2M, and 2N vWD and all type 3vWD patients. Because of the risk of postinfusion thrombocytopenia, DDAVP is contraindicated in type 2B vWD.
· vWF concentrates: Severe bleeding and major surgery in vWD patients require infusion of vWF concentrates typically for 5 to 10 days.
ACQUIRED COAGULATION DISORDERS
Vitamin K Deficiency
· Hepatocytes require vitamin K to complete the synthesis of clotting factors II, VII, IX, and X and the natural anticoagulants protein C and protein S.
· Vitamin K deficiency is usually caused by malabsorption states or poor dietary intake combined with antibiotic-associated loss of intestinal bacterial colonization. Vitamin K deficiency is suspected when an at-risk patient has a prolonged PT that corrects after a 1:1 mix with normal pooled plasma.
· Vitamin K replacement is most commonly given orally or intravenously. With adequate replacement, PT should begin to normalize within 12 hours.
· FFP rapidly but temporarily (4 to 6 hours) corrects acquired coagulopathies secondary to vitamin K deficiency. FFP should only be transfused to patients with active moderate-to-severe bleeding or an impending invasive surgical procedure. Vitamin K is a safer method to manage prolonged PT in patients with no or mild bleeding.
Coagulopathy Due to Anticoagulant Therapy
Supratherapeutic concentrations of anticoagulants may exacerbate bleeding risk. Management, including reversal, is discussed in Chapter 14.
Liver Disease
· Liver disease can seriously impair hemostasis because the liver produces most of the coagulation factors with the exception of vWF.
· Hemostatic abnormalities associated with liver disease typically remain stable unless the liver’s synthetic function rapidly worsens or the patient is not eating normally.
· Hemostatic complications of liver disease are hyperfibrinolysis, thrombocytopenia due to splenic sequestration, DIC, spontaneous bacterial peritonitis, GI hemorrhage, and cholestasis (which impairs vitamin K absorption).
· Transfusion support should be reserved only for cases of moderate-to-severe bleeding or an impending invasive procedure in the setting of additional laboratory abnormalities:
o FFP for severe coagulopathy (PT or aPTT >1.5 times control is often used as a cutoff but is not evidence based)
o Cryoprecipitate, given at a dose of 1.5 units/10 kg body weight, for severe hypofibrinogenemia (<100 mg/dL)
o Platelet transfusion for moderate-to-severe thrombocytopenia
Disseminated Intravascular Coagulation
· DIC occurs in a variety of systemic illnesses, including sepsis, trauma, burns, shock, obstetric complications, and malignancies (notably acute promyelocytic leukemia).
· Exposure of tissue factor to the circulation generates excess thrombin and results in activation and consumption of coagulation factors (including fibrinogen), regulators (protein C, protein S, and antithrombin), and platelets; formation of generalized microthrombi; and reactive fibrinolysis.
· Consequences of DIC include bleeding, organ dysfunction secondary to microvascular thrombi and ischemia, and, less commonly, large arterial and venous thrombosis.27
· Although no one test confirms a diagnosis of DIC, affected patients commonly have prolonged PT and aPTT, thrombocytopenia, low fibrinogen, and a positive D-dimer.
· DIC treatment consists of supportive care, correction of the underlying disorder if possible, and administration of FFP, cryoprecipitate, and platelets as needed for hypofibrinogenemia and thrombocytopenia.
Acquired Inhibitors of Coagulation Factors
· Acquired inhibitors of coagulation factors may arise de novo (autoantibodies) or may develop in hemophiliacs (alloantibodies) following factor VIII or IX infusions.
· The most common acquired inhibitor is directed against factor VIII. Acquired factor VIII inhibitors most commonly occur in patients over 50 years old, during pregnancy, or postpartum or associated with malignancy or autoimmune diseases.
· Patients with coagulation factor inhibitors present with an abrupt onset of bleeding, prolonged aPTT that does not correct after 1:1 mixing, markedly decreased factor activities, and a positive inhibitor titer (Bethesda titer).
· Bleeding complications in patients with factor VIII inhibitors (autoantibodies) are managed in the same manner as for hemophiliacs with alloantibodies to factor VIII (see above Inherited Bleeding Disorders section).
· Eradication of inhibitors consists of immunosuppression with cyclophosphamide, prednisone, rituximab, or vincristine.28
REFERENCES
1.Lippi G, Favaloro EJ, Franchini M, et al. Milestones and perspectives in coagulation and hemostasis. Semin Thromb Hemost 2009;35:9–22.
2.Gewirtz AS, Miller ML, Keys TF. The clinical usefulness of the preoperative bleeding time. Arch Pathol Lab Med 1996;120:353–356.
3.Kirkwood TB. Calibration of reference thromboplastins and standardisation of the prothrombin time ratio. Thromb Haemost 1983;49:238–244.
4.Cines DB, Bussel JB, Liebman HA, et al. The ITP syndrome: pathogenic and clinical diversity. Blood 2009;113:6511–6521.
5.Davoren A, Bussel J, Curtis BR, et al. Prospective evaluation of a new platelet glycoprotein (GP)-specific assay (PakAuto) in the diagnosis of autoimmune thrombocytopenia (AITP). Am J Hematol2005;78:193–197.
6.George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996;88:3–40.
7.Stasi R, Pagano A, Stipa E, et al. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood 2001;98:952–957.
8.Nurden AT, Viallard JF, Nurden P. New-generation drugs that stimulate platelet production in chronic immune thrombocytopenic purpura. Lancet 2009;373: 1562–1569.
9.Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. N Engl J Med 2007;357:580–587.
10.Li X, Hunt L, Vesely SK. Drug-induced thrombocytopenia: an updated systematic review. Ann Intern Med 2005;142:474–475.
11.Furlan M, Robles R, Galbusera M, et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 1998;339:1578–1584.
12.Terrell DR, Williams LA, Vesely SK, et al. The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency. J Thromb Haemost 2005;3:1432–1436.
13.Zheng X, Pallera AM, Goodnough LT, et al. Remission of chronic thrombotic thrombocytopenic purpura after treatment with cyclophosphamide and rituximab. Ann Intern Med 2003;138:105–108.
14.Bresin E, Gastoldi S, Daina E, et al. Rituximab as pre-emptive treatment in patients with thrombotic thrombocytopenic purpura and evidence of anti-ADAMTS13 autoantibodies. Thromb Haemost2009;101:233–238.
15.Ferrara F, Annunziata M, Pollio F, et al. Vincristine as treatment for recurrent episodes of thrombotic thrombocytopenic purpura. Ann Hematol 2002;81:7–10.
16.George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood 2010;116:4060–4069.
17.Atkinson JP, Goodship TH. Complement factor H and the hemolytic uremic syndrome. J Exp Med 2007;204:1245–1248.
18.Tarr PI. Shiga toxin-associated hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: distinct mechanisms of pathogenesis. Kidney Int Suppl 2009;112:S29–S32.
19.Cuker A, Cines DB. How I treat heparin-induced thrombocytopenia. Blood 2012;119:2209–2218.
20.Linkins LA, Dans AL, Moores LK, et al. American College of Chest Physicians. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition). Chest 2012;141:495S–530S.
21.Lo GK, Juhl D, Warkentin TE, et al. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006;4:759–765.
22.Cuker A, Gimotty PA, Crowther MA, et al. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systemic review and meta-analysis. Blood 2012;120:4160–4167.
23.Mannucci PM, Tuddenham EG. The hemophilias—from royal genes to gene therapy. N Engl J Med 2001;344:1773–1779.
24.Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood 1997;90:2515–2521.
25.Sadler JE, Budde U, Eikenboom JC, et al. Working Party on von Willebrand Disease Classification. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost 2006;4:2103–1214.
26.Rodeghiero F, Castaman G, Tosetto A. How I treat von Willebrand disease. Blood 2009;114:1158–1165.
27.Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999;341:586–592.
28.Wiestner A, Cho HJ, Asch AS, et al. Rituximab in the treatment of acquired factor VIII inhibitors. Blood 2002;100:3426–3428.