Platelet Disorders and Hemostatic Emergencies

Shawn K. Kaku and Catherine T. Jamin

BACKGROUND

Hemostasis is the process by which a blood clot is formed at a site of vessel injury. For simplicity, this process may be thought of as occurring in two steps. The first step, primary hemostasis, is the formation of a platelet aggregate at the site of injury. The second step, termed secondary hemostasis, is the activation of the coagulation cascade, which results in the formation of crossed-linked fibrin that strengthens the platelet aggregate. The fibrinolysis system limits the coagulation cascade, thus preventing excess clot formation. A properly functioning hemostatic system requires a functioning liver to synthesize coagulation factors, a sufficient number of platelets and cofactors, and appropriate coordination between the coagulation and fibrinolysis systems. This chapter provides an overview of the etiology and management of hemostatic dysfunction.

HISTORY AND PHYSICAL EXAM

A thorough history and physical will help to identify the etiology of the hemostatic or platelet disorder. In addition to a standard patient history, the provider should review the details of any bleeding events, including triggers, location, frequency, duration, and severity.¹ The physical exam should assess for bruising and petechiae, liver size and stigmata of cirrhosis, joint hemarthrosis, signs of anemia, and evidence of an infection.

Details of the history and physical can indicate a primary or secondary hemostatic disorder. Petechiae, bruising, mucosal bleeding, epistaxis, menorrhagia, and persistent bleeding are suggestive of disorders of platelets or primary hemostasis. Bleeding into soft tissues, muscles, and joints, or delayed bleeding, implies the presence of a coagulation factor deficiency or a disorder of secondary hemostasis.²

PLATELET DISORDERS

Idiopathic Thrombocytopenic Purpura

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder that results in the destruction of platelets through an IgG-mediated antibody. Platelets coated with the antibody are rapidly cleared by macrophages in the liver and spleen.³ ITP is characterized by an isolated thrombocytopenia, defined as a platelet count <100 × 10⁹/L, in the absence of an obvious initiating or underlying cause.^4,5 As there is no gold standard for the diagnosis of ITP, it is considered a diagnosis of exclusion.^4,6 Therefore, a myriad of potential causes of thrombocytopenia must be evaluated prior to diagnosis, including systemic diseases, thrombotic thrombocytopenic purpura (TTP), drug reactions, primary hematologic disorders, liver dysfunction, infections, and recent transfusions.⁶ A secondary form of ITP may also occur in association with underlying conditions such as human immunodeficiency virus, systemic lupus erythematosus, lymphoproliferative disorder, and antiphospholipid syndrome.³

In contrast to the self-limited presentation of ITP that is typical in children, ITP in adults is generally chronic, with a gradual onset.³ Mucocutaneous bleeding, purpura, petechiae, epistaxis, and gum bleeding are the most common initial manifestations.⁴

No definitive evidence exists to guide an exact threshold at which to initiate medical therapy, such as glucocorticoids, in adults with ITP. Most patients will not require therapy; however, it is generally accepted that a platelet count <30 × 10⁹/L should be treated, regardless of the presence of bleeding.⁵ Therapy must be individually tailored, and the decision to treat should weigh the patient’s risk of bleeding—that is, previous bleeding episodes, age, presence of other comorbidities, level of activity, etc.⁶

In the critically ill patient with ITP and hemorrhage, initial therapy consists of high-dose intravenous steroids, such as methylprednisolone (30 mg/kg/d × 3 days for children and 1 g/day × 3 days for adults). Intravenous immunoglobulin (IVIG) 1 g/kg and transfusions may also be used.^5,6 Although the exact mechanism of IVIG in treating ITP remains to be elucidated, it is thought to play a role in preventing the uptake of antibody-coated platelets through the blockage of the Fc receptor on macrophages.⁷ Platelet transfusion is not typically advised in the treatment of ITP, since any transfused platelets will eventually also be destroyed by circulating autoantibodies. However, platelet transfusions have been shown to help sustain the treatment response and may temporarily aid hemostasis in the bleeding patient.^7,8 The use of anti-Rho(D) immune globulin (anti-D) has been shown to be effective, though only in Rh-positive patients who have not had a splenectomy.⁹ The anti-D binds Rh-positive erythrocytes, occupying the receptor in the splenic macrophages that would otherwise be used for removal of platelets. Emergency splenectomy may also be considered. As a nonemergent second-line therapy, splenectomy is associated with an 80% response rate.⁶ Its use in an emergency situation must be individualized, as the bleeding thrombocytopenic patient makes a challenging ideal surgical candidate.

Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a life-threatening disorder caused by antibodies against complexes of heparin bound to platelet factor IV. It should be suspected when a patient has a low platelet count, or at least a 50% drop in the platelet count, approximately 5 to 10 days after heparin exposure.^10,11 The frequency of HIT is 1% to 5% when unfractionated heparin is used and <1% with low molecular weight heparin (LMWH).¹⁰ Although HIT causes thrombocytopenia, thrombosis—not bleeding—is the major clinical concern.¹⁰ This is due to platelet activation and the generation of platelet microparticles that leads to thrombin generation and thrombosis.^11,12 Thrombotic complications develop in approximately 20% to 50% of patients and can persist for days to weeks after heparin therapy is stopped.¹¹ Complications include arterial and venous thrombosis, limb ischemia, and cerebral venous sinuses thrombosis.¹¹

The laboratory testing for HIT includes a heparin–platelet factor 4 (H-PF4) ELISA antibody test and functional assay tests. The H-PF4 test is widely available and often the first diagnostic test sent. The functional assay tests, while becoming more common, are not always available and are often send-out tests that require up to a week to result. The H-PF4 test has a high sensitivity (>97%) but a poor specificity (74% to 86%), as only a subset of these detected antibodies can cause HIT.¹¹ This is especially true in surgical patients; up to 20% to 50% of postoperative cardiac patients and 81% of surgical ICU patients can have a false positive H-PF4.^10,12 Given the high negative predictive value of the H-PF4 test, patients deemed to have a high to intermediate risk of HIT with a negative H-PF4 should be evaluated for alternative diagnoses of their thrombocytopenia.¹¹

The heparin-induced platelet aggregation test is a functional assay test, with a sensitivity of >90% and a specificity ranging from 77% to 100%.¹¹ The c-serotonin functional assay test measures serotonin release from activated platelets and is considered the “gold standard” for the diagnosis of HIT, with a sensitivity and specificity of >95%.^11,13–15 Unfortunately, this test is often not available in the emergency department (ED).

Waiting for the send-out test to confirm a diagnosis of HIT can be problematic, given both the dangers of treatment delay and the potentially serious side effects of the treatment itself. The “4Ts” clinical scoring system shown in Table 29.1 provides a real-time evaluation of HIT.¹⁶ A recent meta-analysis confirmed its utility in a wide range of patient population, demonstrating a negative predictive value of 99.8% for those with a low score.¹⁷

Treatment of HIT—to suppress thrombotic events—consists of stopping all sources of heparin, including LMWH, and initiating an alternate form of systemic anticoagulation. There are currently three FDA–approved medications for the treatment of HIT: argatroban, bivalirudin, and lepirudin; however, the manufacture of lepirudin has recently been discontinued. While there are no prospective randomized studies examining their efficacy, argatroban has shown superior efficacy in two prospective trials compared to historical controls in reducing thrombotic events and death from thrombosis without an increase in bleeding rates.^18,19 Argatroban should be dose adjusted in patients with hepatic dysfunction. Bivalirudin is approved only for patients with HIT undergoing percutaneous coronary intervention. The American College of Chest Physician (ACCP) guidelines notes that fondaparinux may have a theoretical role in treating HIT; at this time, however, it is not approved for this use.²⁰

Patients with HIT are in a prothrombotic state and should remain on anticoagulation for 4 to 12 weeks after diagnosis; this may be accomplished via transition to warfarin therapy.²⁰ The initiation of warfarin must be done cautiously, as warfarin rapidly decreases protein C levels, which can exacerbate the prothrombotic state and lead to skin necrosis and limb gangrene.²⁰ The 2012 ACCP guidelines recommend starting warfarin only after the patient shows platelet recovery of at least 150 × 10⁹/L and stable anticoagulation on thrombin inhibitors; if warfarin has already been started when a patient is diagnosed with HIT, then vitamin K should be administered until the above criteria are met.²⁰ Finally, since spontaneous bleeding is uncommon with HIT, platelets should be transfused only in patients who are bleeding or during the performance of an invasive procedure with a high risk of bleeding.²⁰

HELLP Syndrome

HELLP syndrome is a serious complication of pregnancy, characterized by hemolysis (H), elevated liver enzymes (EL), and low platelets (LP). Controversy exists as to whether HELLP is a severe manifestation of preeclampsia or a separate disease process. Although it can occur earlier, HELLP syndrome usually presents after 28 weeks’ gestation.¹⁰ Classic symptoms include epigastric or right upper quadrant abdominal pain, nausea, and vomiting.^21,22 Patients also may have nonspecific symptoms, such as malaise or headache, which can be mistaken for a viral syndrome.^21,22 Although there is no consensus on laboratory values for the diagnosis of HELLP syndrome, patients ideally should demonstrate all components of its acronym, namely, microangiopathic hemolytic anemia (MAHA), EL, and decreased platelets.^10,21,22

HELLP syndrome increases the chance of maternal death and is associated with disseminated intravascular coagulopathy, abruptio placentae, severe postpartum bleeding, pulmonary and cerebral edema, liver infarct and rupture, and cerebral infarcts and hemorrhages.^21,22 While delivery of the fetus is the cornerstone of treatment, the exact timing of delivery is unclear and is dependent on the gestational age as well as the stability and condition of the mother and fetus.^21,22 Laboratory abnormalities may reverse in a subgroup of patients who are managed expectantly; however, this approach needs to be more rigorously investigated.^23,24 All patients with HELLP syndrome should be admitted to the hospital and treated for severe preeclampsia, with intravenous magnesium as prophylaxis against convulsions and antihypertensive medications to keep systolic blood pressure below 160 mm Hg, diastolic blood pressure below 105 mmHg, or both.²² Corticosteroid administration to aid fetal lung maturation is often recommended if the fetus is between 24 and 34 weeks’ gestational age.²² Platelets should be transfused for significant bleeding or platelet counts <20 × 10⁹/L.²² The use of corticosteroids to improve maternal outcome remains controversial and experimental, as the benefits seen by early small randomized and observational studies could not be reproduced in two larger, randomized, double-blind, placebo-controlled trials.^25,26

Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome

TTP and hemolytic uremic syndrome (HUS) describe two diseases of a broader category called thrombotic microangiopathies. The thrombotic microangiopathies are microvascular occlusive disorders characterized by aggregation of platelets, thrombocytopenia, and mechanical injury to erythrocytes.²⁷ While sharing similar characteristics, the adult form of TTP and the childhood form of diarrheal HUS are two separate disorders.

TTP is thought to be due to a deficiency of the ADAMTS13 enzyme, with an inhibitory antibody being the cause in the majority of the classic cases.¹⁰ The ADAMTS13 enzyme is responsible for cleaving the newly synthesized von Willebrand factor (vWF) multimer. When not cleaved, these unusually large vWF multimers lead to spontaneous platelet aggregation and the clinical syndrome of TTP.¹⁰ TTP can be both congenital and acquired, with the congenital form being extremely rare. While the majority of acquired causes are idiopathic, examples of secondary causes of TTP include medications, infections, pregnancy, lupus, malignancy, and transplantation.²⁸

The classic pentad of TTP is thrombocytopenia, MAHA, fluctuating neurologic signs, renal impairment, and fever²⁷ MAHA is caused by erythrocytes passing through areas of the microcirculation that are partially occluded by aggregated platelets.²⁷ This causes fragmented erythrocytes, termed schistocytes or helmet cells, as well as elevated lactate dehydrogenate and indirect bilirubin.^27,28 Some patients, however, may not present with neurologic symptoms, renal failure, or fever. Therefore, the diagnosis of TTP may be made in the presence of an MAHA and thrombocytopenia in the absence of any other identifiable cause.²⁸

Treatment for TTP should be initiated even if diagnostic uncertainty exists, as the untreated mortality rate can be as high as 95% to 100%.^29–31 Plasma exchange, or the removal of a patient’s plasma and replacement with another fluid (donor plasma, colloid, etc.), is the mainstay of treatment, as it removes the inhibitory antibody and supplies new ADAMTS13. Plasma exchange has decreased the TTP mortality rate to <20%.^10,27–31 While not as effective as plasma exchange, plasma infusion alone has been shown to decrease the mortality rate to 37%.^28,32 Therefore, plasma infusion (30 mL⁄kg⁄d) may be indicated as the initial treatment if there is to be an unavoidable delay in plasma exchange.²⁸ Although steroids have been widely used for TTP as an adjunctive immunosuppressive treatment, there is minimal evidence for their efficacy and no consensus on dosing or route.²⁸ Since patients may benefit from their use, steroids can be given as adjuvant therapy. A reasonable approach is methylprednisolone 2 mg⁄kg⁄d, although pulse doses of 1 g/day × 3 days may also be used.²⁸ Rituximab, an anti-CD20 antibody, should be considered for patients refractory to plasma exchange.^33,34 Platelet transfusions are contraindicated as they can worsen the platelet aggregation and effects of TTP. They should be reserved for life-threatening hemorrhage or for invasive procedure preparation.²⁸

HUS is characterized by MAHA, thrombocytopenia, and acute renal failure. HUS is commonly associated with a prodrome of bloody diarrhea caused by the Shiga toxin–producing Escherichia coli 0157:H7.^27,28 The toxin damages endothelial cells, causing platelet aggregation and intravascular thrombogenesis. Much of the treatment for HUS is supportive in nature. The optimal care requires careful management of fluid and electrolyte balance and blood pressure. The use of hemodialysis may be required if renal failure is severe.²⁸ Antibiotics and antimotility agents should be avoided as they can worsen the outcome.^27,28 Two prospective studies on plasma infusion in HUS failed to show any outcome benefit.^35,36 There are no randomized controlled prospective studies evaluating the use of therapeutic plasma exchange for HUS caused by Shiga toxin–producing Escherichia coli, and it is currently reserved only for severe cases, often those involving the nervous system. As in the case of TTP, blood transfusion for HUS should be given based on clinical evaluation and need, rather than on a strict hemoglobin threshold; platelet transfusions should be avoided if possible.

DISORDERS OF COAGULATION

Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is characterized by the widespread activation of the coagulation cascade, which results in fibrin formation, thrombotic occlusion of small and midsize vessels, and subsequent organ failure. Simultaneously, the consumption of platelets and coagulation proteins can induce severe bleeding.³⁷ DIC is not a disease in itself but is instead a complication of an underlying disorder. These disorders include sepsis, trauma, organ dysfunction (pancreatitis), obstetric emergencies, malignancy, and toxic and transfusion reactions.³⁸

No single laboratory test can diagnose or rule out DIC. Instead, in a patient at risk for DIC, a combination of test results can be used to diagnose the disorder with reasonable certainty.³⁷ Common laboratory abnormalities include thrombocytopenia, elevated fibrin degradation products, prolongation of clotting times including the prothrombin time (PT) and the activated partial thromboplastin time (PTT), and a low fibrinogen.^37,39 Schistocytes may also be present on the blood smear.³⁷ Caution must be exercised when interpreting fibrinogen levels, as it is an acute-phase reactant that can remain within the normal range or elevated for a long period of time.^37,39

The cornerstone of treatment of DIC is treatment of the precipitating condition.^37–39 Transfusion of platelets or plasma should be reserved for patients with active or high risk of bleeding. Platelet transfusion is indicated in bleeding patients with platelet counts <50 × 10⁹/L and in nonbleeding patients with platelet counts <10 to 20 × 10⁹/L.³⁹ Fresh frozen plasma (FFP) and/or cryoprecipitate are recommended for patients who are bleeding with an INR > 2 or a fibrinogen level <100 mg/dL.⁴⁰ In cases of DIC where a thrombotic picture predominates (e.g., arterial or venous thromboembolism, severe purpura fulminans, or vascular skin infarctions), therapeutic doses of heparin should be considered.³⁹ In critically ill, nonbleeding patients with DIC, prophylaxis for venous thromboembolism with heparin or LMWH is recommended.³⁹ The use of antithrombin (formerly antithrombin III) has not improved outcomes in DIC, and further investigation is warranted in the use of recombinant human factor VIIa.^41,42 For patients with inherited or acquired protein C deficiencies, protein C concentrate has demonstrated some benefit.⁴³

HEMOPHILIA

Hemophilia is an X-linked heritable coagulopathy, most often referring to a deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B, Christmas disease). While these deficiencies are difficult to distinguish clinically, factor VIII deficiency comprises approximately 80% of cases and factor IX deficiency the remaining 20%.^44,45 The severity of hemophilia is defined by the level of serum clotting factors as compared to the general population: <1% of normal is defined as severe, 1% to 5% of normal as moderate, and >5% of normal as mild.^44,46 Patients with hemophilia are at risk for hemarthrosis (especially knee, ankle, and elbow joints), soft tissue hematomas, bruising, retroperitoneal bleed, intracranial hemorrhage, and postsurgical bleeding.^44,47

Due to the heritability of the disease, a family history of hemophilia or abnormal bleeding is extremely helpful in making the diagnosis. Approximately 30% of cases, however, have no known family history and are caused by spontaneous mutations. Laboratory values for patients with hemophilia A and B will demonstrate normal platelets and PT, with a prolonged PTT. Specific assays for each factor can be used to identify the type of hemophilia.

Administration of the deficient factor is needed to limit or stop an episode of bleeding. The amount of factor replaced is dependent on the location of the bleeding. According to the guideline from the World Federation of Hemophilia, a factor level of 40% to 60% is recommended for deep lacerations, joint, and most muscle bleeding, and a factor level of 80% to 100% is recommended for CNS, throat and neck, GI, and iliopsoas muscle bleeding.⁴⁸ The formulas for estimating the dose of factor required to be administered are shown in Table 29.2. If unknown, the baseline factor should be presumed to be 0%. The patient’s replaced factor level should be measured approximately 15 minutes after infusion to verify calculated doses.⁴⁸ The half-life of factors VIII and IX is 8 to 12 hours and 18 to 24 hours, respectively. Redosing will be needed at that time.⁴⁸

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