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Disorders of primary hemostasis have a vast differential diagnosis and may present in a variety of medical, obstetric, surgical, and critical care settings. When evaluating patients with thrombocytopenia or evidence of qualitative platelet dysfunction, clinicians must determine the significance of the platelet count as well as the risk for bleeding, thrombosis, and other potential complications. In one study, thrombocytopenia was observed in approximately 1% of adult inpatients in acute care hospitals.1 Surgical bleeding is of concern when platelet counts are <50,000/µL, or <100,000/µL in patients undergoing some high-risk cardiac, orthopedic, or neurosurgical procedures.2 In intensive care units (ICUs), thrombocytopenia develops in 13% to 44% of patients during their admission.2 Clinicians must be familiar with the conditions leading to disorders of primary hemostasis because swift, accurate identification of the underlying cause is crucial for appropriate management. This article reviews disorders of primary hemostasis that range in severity from benign to life-threatening, focusing on pathophysiology, distinguishing features, diagnostic assessment, and treatment.
Physiology of primary hemostasis
Megakaryocytes, which are derived from hematopoietic stem cell precursors in bone marrow, form and release platelets; these circulate in the blood for 8 to 10 days before they are removed by hepatic or splenic macrophages. The concentration of circulating platelets is normally 150,000 to 450,000/µL. A platelet count <150,000/µL traditionally defines thrombocytopenia; however, 2.5% of the population has a baseline concentration <150,000/µL.2 Clinicians should repeat the platelet count for trending; if the count is stable for 6 months, it is usually a normal variant.1 Normal vascular endothelium opposes thrombosis by resisting interactions with platelets and coagulation factors. Damage to vessels exposes collagen fibrils that trigger a series of adhesive reactions, allowing platelets to bind to the subendothelium and to other platelets to form a temporary hemostatic plug. A large protein, von Willebrand factor (vWF), is synthesized, stored in, and secreted by vascular endothelial cells following stimulation. Plasma vWF binds platelets to the subendothelial collagen via its platelet glycoprotein Ib complex. Platelets also have receptors that bind directly to collagen. Normal engagement of these receptors enhances platelet activation and signals extension of the plug. Activated platelets release pro-aggregatory granules containing adenosine 5′-diphosphate (ADP) and thromboxane A2 to amplify recruitment and aggregation. Fibrinogen and vWF also bind activated platelets together via the platelet glycoprotein IIb/IIIa complex. The hemostatic plug stops bleeding in a superficial wound. Initiation of the clotting cascade triggers secondary hemostasis, which culminates in the formation of a fibrin mesh that cross-links, reinforces, and further stabilizes the platelet plug. As a carrier protein for clotting factor VIII, vWF also functions in secondary hemostasis by protecting this factor from degradation.
Manifestations of disorders of primary and secondary hemostasis
Platelets play an essential role in preserving vessel wall integrity. Deficiency or dysfunction of platelets cause defects in primary hemostasis, characterized by superficial mucocutaneous bleeding and a prolonged bleeding time. Petechiae result from capillary bleeding and are likely to develop on dependent body regions. Confluence of petechiae results in the formation of purpura, which is “dry” when located on the skin and “wet” when located on mucous membranes. Wet purpura signifies potentially more serious hemorrhage.2 The common bleeding manifestations of primary hemostasis disorders (Table 1) occur frequently in many of the disorders discussed in this review. Because the normal values for platelets are >150,000/µL, the blood has a large protective reservoir. Mild thrombocytopenia is defined by platelet levels of 100,000 to 150,000/µL, moderate thrombocytopenia by levels of 50,000 to 100,000/µL, and severe thrombocytopenia by levels <50,000/µL. Significant spontaneous bleeding usually does not occur until platelet counts are <10,000 to 20,000/µL.1 Severe thrombocytopenia confers a greater risk for bleeding, but correlation between the platelet count and risk for bleeding varies with the underlying condition. Comparatively, clotting factor deficiency or dysfunction results in disorders of secondary hemostasis and may cause delayed, deep, or prolonged bleeding. Bleeding into the central nervous system (CNS), hemarthrosis (bleeding into the fingers, wrists, knees, feet, and spine), deep muscle hematomas, or retroperitoneal bleeding usually indicates a clotting factor disorder. Clinically, no specific type, location, or quantity of bleeding is certain to differentiate a primary from a secondary disorder of hemostasis, and both can be severe, even life-threatening. Laboratory testing will reveal a prolonged bleeding time with or without thrombocytopenia in a disorder of primary hemostasis; disorders of secondary hemostasis are characterized by prolongation of the partial thromboplastin time (PTT) with or without prolongation of the prothrombin time (PT), depending on the clotting factors affected. In disorders of secondary hemostasis, the bleeding time and platelet count will be normal. Disorders of secondary hemostasis are outside the scope of this article but may be discussed in the differential diagnoses as appropriate.
History and physical examination
The history and physical examination are imperative to guide the differential diagnosis and focus the laboratory assessment. Conduct a full mucocutaneous survey to search for signs of platelet dysfunction, and carefully assess the patient for hepatosplenomegaly, lymphadenopathy, and/or signs of thrombosis because the presence of these abnormalities influences the workup. Inquire about easy bruising or excessive bleeding, determine the location and duration of bleeding and whether it occurs spontaneously or after trauma (immediate vs delayed), and assess for evidence of volume loss or anemia. Extensive bruising or bruising in unusual locations where trauma is less likely (trunk, inner arms, thighs) is suspect. Obtain previous platelet counts if possible to determine if the level is stable or decreasing. An acute drop in the platelet count of >50%, even if the count is still within normal range, may herald a severe disorder and requires close follow-up.2 Lifelong bleeding or a family history of a bleeding disorder may indicate a familial or congenital disorder. Congenital platelet defects are strongly associated with consanguinity. Bleeding should not be overlooked in the elderly because age-related changes in hemostasis parameters (shortened bleeding time and PTT; increased levels of factors II, VIII, and X; and decreased levels of antithrombin III) favor thrombosis, not bleeding. Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and anticoagulants are common causes of bleeding or factors that exacerbate bleeding in the elderly. Clinicians may use a validated, objective bleeding score, such as the one derived from the Condensed MCMDM-1 VWD Bleeding Questionnaire,3 which grades the worst episode for each of the following: epistaxis; cutaneous manifestations; bleeding from minor wounds or the oral cavity; gastrointestinal bleeding; bleeding following tooth extraction or surgery; menorrhagia; postpartum hemorrhage; muscle hematoma; hemarthrosis; and CNS bleeding.4,5 The higher the bleeding score, the greater the likelihood of a bleeding disorder. In von Willebrand disease (vWD), the most common bleeding disorder, a score >4 has a sensitivity of 100% and a specificity of 87%, with a positive predictive value of 0.2.5 Uneventful molar tooth extraction is unlikely in a patient with a severe bleeding disorder.6
Assess for past medical history and for underlying diseases or their risk factors, particularly the following:
- Autoimmune and connective tissue disorders: systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid syndrome
- Blood disorders and/or malignancy: leukemia, lymphoma, myeloproliferative disorders
- Infections: human immunodeficiency virus (HIV) infection; hepatitis A, B, or C; disease caused by cytomegalovirus; other viral or rickettsial disease
- Recent vaccinations; medication use (prescribed, over-the-counter, and alternative medications)
- Pregnancy status, recent transfusion, surgery or organ transplant
- Recent travel (malaria, rickettsial infection, leptospirosis, dengue or viral hemorrhagic fever)
- Alcohol and drug use, liver or kidney disease
A variety of infections may induce thrombocytopenia via immune-mediated platelet destruction, bone marrow suppression, or platelet consumption. In many viral infections (eg, rubella; mumps; varicella; infection with parvovirus, Epstein-Barr virus, or cytomegalovirus), thrombocytopenia is an incidental finding and spontaneously resolves with recovery. In some chronic infections, however, such as those caused by Helicobacter pylori, HIV, or hepatitis C virus (HCV), the thrombocytopenia may persist.2 Adults with the new onset of isolated thrombocytopenia should be screened for these chronic conditions. In many vector-borne diseases (eg, malaria, babesiosis, brucellosis, and anaplasmosis), thrombocytopenia is part of the clinical constellation, and parasites may be seen on peripheral blood smear.
Clinicians should know the mechanism and duration of action of common medications that affect platelet function. Aspirin irreversibly inactivates cyclooxygenase in platelets, and the effect lasts for the lifetime of the platelets. Bleeding time generally normalizes within 3 days after the discontinuation of aspirin. NSAIDs competitively inhibit cyclooxygenase, and the effect is related to the drug half-life, usually 1 day. Clopidogrel irreversibly inhibits the P2Y12 ADP receptor on platelets, impairing the activation of platelets and cross-linking of fibrin. The bleeding time gradually returns to baseline within about 5 days after the discontinuation of clopidogrel. Anticoagulants (heparin, warfarin, dabigatran, apixaban, rivoraxaban) and antiplatelet agents increase the tendency for bleeding and impair hemostasis at sites of hemorrhage. This is particularly important in the management of victims of head trauma. A strong index of suspicion is required in managing mild head trauma in patients treated with anticoagulants to minimize the risk for missed intracranial bleeding.
Alcohol abuse may cause thrombocytopenia through direct bone marrow toxicity, nutrient deficiencies, or hypersplenism. Binge drinking may precipitate severe thrombocytopenia, particularly in those with alcoholic liver disease.6 Deficiency of the nutrients required for hematopoiesis (folate, vitamin B12, copper) secondary to malnutrition, veganism, or bariatric or gastrointestinal surgeries usually induces pancytopenia, but isolated thrombocytopenia may be seen.2 Similarly, clinicians will see thrombocytopenia in bone marrow disorders (myelodysplastic syndromes, infections, sepsis, or infiltrative disease) in which pancytopenia is expected. Classification of thrombocytopenia as an isolated blood cell deficiency or as part of a constellation of pancytopenia is imperative in guiding the differential diagnosis. Uremia is a common cause of qualitative platelet dysfunction and is related to several dialyzable platelet-inhibitory factors that cause the bleeding time to be very prolonged. Gastrointestinal bleeding is the most frequent bleeding symptom, and vigorous dialysis is used to treat the manifestations.
Clinicians may also generate a differential diagnosis for platelet disorders by categorizing the mechanism of platelet loss or dysfunction (Table 2).
The first step in the assessment of primary hemostasis disorders is a review of the platelet count, bleeding time, PT, and PTT, in addition to a careful examination of the peripheral blood smear. Some authors suggest that the basic laboratory evaluation should also include liver and renal function tests, a coagulation panel with D-dimer, and measurement of the lactate dehydrogenase (LDH) level. Historically, bleeding time was quantified by measuring the hemostasis time in a fresh, superficial cut to the volar forearm. This test is unreliable and its use discouraged; it has largely been replaced by objective closure time assays such as the PFA-100 (Platelet Function Analyzer). Prolonged bleeding time indicates a disorder of primary hemostasis. The platelet count will then determine if the disorder is a qualitative dysfunction (the patient has normal platelet counts) or a quantitative dysfunction (thrombocytopenia is present). The bleeding time is generally prolonged with platelet counts <75,000/µL.6 Platelet aggregation tests can distinguish disorders of platelet function and are discussed below together with the relevant diseases. In disorders of secondary hemostasis, such as hemophilia, the bleeding time is usually normal.
The PT and PTT may be prolonged in patients with a clotting factor deficiency or dysfunction. The PT evaluates the activity of the extrinsic and common pathway factors of the clotting cascade and is prolonged in patients with a deficiency of these factors, most notably factor VII. The PTT evaluates the activity of the intrinsic and common pathway clotting factors; hemophilia, for example, will cause prolongation of the PTT, but the PT will be normal. In some coagulopathies, multiple clotting factors are consumed, prolonging both the PT and PTT.
The peripheral blood smear may show morphologic abnormalities relevant to an underlying diagnosis. If thrombocytopenia is due to platelet destruction, large or giant platelets may be seen in addition to platelets of normal size. Fragmented red blood cells (schistocytes) suggest thrombotic microangiopathy, and teardrop-shaped cells (dacryocytes) suggest myelofibrosis. Blast cells are seen in acute leukemia, atypical lymphocytes in various viral infections, and rouleau formation in multiple myeloma. Clinicians should consider that conditions such as bone marrow failure and acute leukemia rarely present with isolated thrombocytopenia. Bone marrow analysis is reserved for patients with thrombocytopenia of unclear etiology, an atypical or a prolonged course, suspected malignancy, or a worrisome abnormality (hepatosplenomegaly, lymphadenopathy, or pancytopenia). A normal or increased number of megakaryocytes on bone marrow analysis accompanied by large platelets in the peripheral blood suggests that thrombocytopenia is due to peripheral platelet destruction and that marrow activity is normal or compensatory. A decreased number of megakaryocytes and decreased bone marrow cellularity suggest bone marrow failure or aplastic anemia.
How swiftly a subsequent evaluation should take place depends on the patient’s presentation and platelet count. If the patient is symptomatic with acute bleeding or the level of thrombocytopenia confers a high risk for bleeding, an assessment should be performed immediately. Otherwise, outpatient testing can occur over 1 to 2 weeks, with the patient counseled that he or she should return immediately or report to an emergency department if any changes in clinical status or bleeding occur. Patient education is imperative in the management of congenital platelet disorders or moderate to severe thrombocytopenia. Mucocutaneous bleeding is common, but serious hemorrhage requires immediate treatment, and clinicians should review a plan of action with patients. Patients should avoid medications that interfere with platelet function (aspirin, NSAIDs, ginko biloba) and should not engage in extreme athletics (football, boxing, rugby, martial arts). Women with severe menorrhagia may benefit from hormonal suppression of the menses.
Differential diagnosis of disorders of primary hemostasis
Von Willebrand Disease. vWD, the most common inherited bleeding disorder, is caused by a deficiency or qualitative abnormality of vWF. vWD affects about 1 in 1000 persons6 or 0.5% to 1.6% of the population in Western countries.7 It has an autosomal-dominant or autosomal-recessive inheritance and is equally distributed between the sexes. vWD results in defective platelet adhesion to the vascular subendothelium and may lead to the degradation of coagulation factor VIII in the circulation. Manifestations vary, with bleeding that ranges from mild to life-threatening. Patients have bleeding manifestations (Table 1) with normal platelet counts and a prolonged bleeding time.
vWD is classified as follows: partial quantitative deficiency (type 1: 60%-80% of cases per Western data distribution), qualitative dysfunction (type 2: 7%-30% of cases), and total deficiency (type 3: 5%-20% of cases).7 Patients should be at optimal baseline for laboratory testing because stressors (illness, anxiety, recent exercise, acute inflammation) and estrogen (pregnancy and oral contraceptives) may transiently elevate vWF and factor VIII levels.5 Accurate subtyping of vWD requires laboratory investigations including, but not limited to, quantitative vWF antigen (vWF:Ag) level, vWF ristocetin cofactor activity (vWF:RCo), and factor VIII levels. The vWF:RCo measures the ability of plasma to agglutinate platelets in the presence of ristocetin, which is proportional to the hemostatic activity of vWF. Defective aggregation with ristocetin is the characteristic abnormality in vWD. Levels of vWF:RCo <30 IU/dL are designated as definitive for vWD, although some patients with type 2 vWD have higher levels.5 A very simplified analysis of the variables used to determine the type of vWD appears in Table 3. In type 1 vWD, the plasma vWF level (vWF:Ag) is low but sufficient to mediate some platelet adhesion (vWF:RCo) and stabilize factor VIII levels. Type 1 vWD is asymptomatic and may result in relatively mild bleeding symptoms. Type 3 vWD is characterized by undetectable vWF:Ag and vWF:RCo and factor VIII levels usually <10 IU/dL7 with prolonged PTT and risk for bleeding indistinguishable from that of hemophilia A. Type 2 vWD is subdivided into four variants (2A, 2B, 2M, 2N) on the basis of specific defects that impair platelet adhesion or factor VIII binding. In-depth factor ratios, collagen binding studies, mutation analysis, and inhibitor assays are required to distinguish the type 2 vWD subtypes.
For patients with type 1 vWD, the preferred prophylaxis in anticipation of minor surgery or dental procedures is intravenous or intranasal desmopressin (DDAVP), which stimulates the release of vWF from endothelial cells. A trial dose of DDAVP is given before anticipated use to determine responsiveness. Therapy should achieve a vWF:RCo level >30 IU/dL, preferably >50 IU/dL, and DDAVP should be discontinued 2 to 3 days after the procedure to prevent tachyphylaxis.5,6 Most patients with type 1 vWD respond to DDAVP, but if the response is inadequate, vWF concentrates should be used. For severe bleeding or prophylaxis before major surgery, patients receive vWF concentrates or cryoprecipitate. The target VWF:RCo level is >100 IU/dL; levels >50 IU/dL should be maintained for at least 7 to 10 days.5 Factor VIII levels often rise following the infusion of vWF concentrate and remain elevated for about 40 hours, reflecting the half-life of vWF.6
Bernard-Soulier syndrome and Glanzmann thrombasthenia. If vWD is ruled out, additional aggregation tests can define the platelet defect in qualitative platelet disorders. Bernard-Soulier syndrome (BSS) and Glanzmann thrombasthenia are rare, autosomal-recessive congenital disorders associated with a history of familial consanguinity and may cause lifelong bleeding manifestations (Table 1). In BSS, a molecular defect alters the platelet glycoprotein complex Ib/IX/V, preventing the normal adhesion of platelets to vWF and to ristocetin, although the platelets aggregate normally in response to other agonists (ADP, collagen, epinephrine). Patients have a prolonged bleeding time and more severe bleeding than expected for the mild thrombocytopenia associated with the condition. Giant circulating platelets are seen on peripheral smear. The severity of bleeding in BSS varies; the prognosis is related to the severity of the disease, which may change over time in response to hormones and aging.8 Glanzmann thrombasthenia results from deficiency or dysfunction of the platelet glycoprotein IIb/IIIa complex. Platelets can adhere to exposed subendothelium and aggregate with ristocetin but have a limited ability to form platelet microthrombi without the ability of this receptor to bind vWF and fibrinogen. Typically, aggregation tests show poor aggregation to ADP, epinephrine, collagen, and thrombin. Absent or severely reduced platelet aggregation leads to a prolonged bleeding time and severe mucocutaneous bleeding despite the normal numbers and size of platelets. In cases of severe bleeding, platelet transfusions are usually effective, but the benefit-to-risk ratio should be evaluated. Repeated exposure to normal platelets in conditions in which platelet glycoprotein is absent (BSS or Glanzmann thrombasthenia) can result in the development of autoantibodies to the missing proteins. This renders subsequent transfusions of normal platelets ineffective. To minimize sensitization, blood products should have few or no leukocytes.8 Bone marrow transplant has been used in rare cases of serious, repetitive bleeding.
Idiopathic thrombocytopenic purpura. The two most common causes of isolated thrombocytopenia are idiopathic thrombocytopenic purpura (ITP) and drug-induced thrombocytopenia (DIT).1 In ITP, platelet autoantibodies (immunoglobulin G, or IgG) to the target of the platelet glycoprotein IIb/IIIa complex are produced. Once tagged, the platelets are damaged, trapped in the spleen, and removed from the circulation. Additionally, antibodies may interact with megakaryocytes in bone marrow, suppressing thrombopoiesis. ITP commonly occurs in persons with other autoimmune disorders and in patients with chronic HIV or HCV infection. All adult patients with newly diagnosed ITP should undergo screening for HIV and HCV infection.9 The acute, self-limited form of ITP has no gender predilection, is usually observed in healthy children (5/100,000 persons6) 3 to 5 years of age, and may follow a viral upper respiratory infection. The chronic form of ITP occurs in adults 20 to 50 years of age (3/100,000-5/100,000 persons6), has an insidious onset, often persists for longer than 6 months, and has a female predilection. Bleeding manifestations (Table 1) vary depending on the platelet count. ITP usually causes no constitutional symptoms (weight loss, bone pain, night sweats), lymphadenopathy, or hepatosplenomegaly. The presence of splenomegaly or these other findings suggests another condition. Abdominal ultrasound may support ITP by ruling out chronic liver disease with hypersplenism and the presence of organomegaly or abdominal lymphadenopathy.1 Peripheral blood smear will show giant platelets reflective of thrombopoietin-induced bone marrow stimulation, and antiplatelet IgG assays are about 90% specific for ITP.1 The American Society of Hematology (ASH) guidelines consider bone marrow studies unnecessary regardless of age in patients with typical features of ITP.
Overall, >80% of untreated children exhibit spontaneous remission within 2 to 8 weeks.10 The rest have a course similar to that of individuals with adult-onset, chronic ITP. In children, factors associated with the development of chronic ITP include the following: female gender, age >11 years at onset, lack of precedent infection/vaccination, insidious onset, presence of antinuclear antibodies, and treatment with intravenous immunoglobulin (IVIG) plus steroids vs IVIG alone.10 The ASH guidelines specify that children with mild mucocutaneous bleeding require only observation, regardless of the platelet count. In children who require therapy, a single dose of IVIG or a short course of corticosteroids is first-line treatment. There is no evidence supporting the benefit of a prolonged course of steroids rather than very brief courses in children.9 IVIG is preferred over steroids if a rapid increase in the platelet count is desired, although the combination of IVIG with high-dose dexamethasone is synergistic in cases of imminent hemorrhage.6 The risk for intracranial hemorrhage in children with ITP is minimal (<0.1%), and intracranial hemorrhage generally occurs with platelet counts <20,000/µL.6 Platelet transfusions are used supportively if the platelet counts are <20,000/µL. Anti-D immunoglobulin (anti-D) is first-line treatment in Rh-positive children with an intact spleen, but the Food and Drug Administration (FDA) cautions about risk for severe hemolysis, and anti-D should not be used if post-hemorrhagic anemia or autoimmune hemolysis is present. Children with refractory ITP and significant or persistent bleeding may be candidates for rituximab, high-dose dexamethasone, or splenectomy. Because spontaneous remission is so common, splenectomy should be avoided in children younger than 6 years of age because of future risk of severe sepsis.6 The ASH guidelines recommend splenectomy only if a child has had ITP for longer than 1 year with bleeding and platelet counts <30,000/µL.
Only 2% of adults with ITP have a spontaneous remission, but 60% to 90% respond to first-line therapy.10 Adults should be treated when the platelet counts are <30,000/µL, or higher in those with active bleeding or a risk for bleeding (eg, peptic ulcer disease, hypertension). In adults, longer courses of steroids are preferred over shorter courses or IVIG.9 IVIG may be paired with steroids if a rapid rise in platelets is required. Anti-D is as effective as IVIG in Rh-positive adults with an intact spleen, and either may be used as first-line therapy in adults if steroids are contraindicated. Second-line therapies for adults include splenectomy, rituximab, thrombopoeitin receptor agonists, or more potent immunosuppression. The platelet response to thrombopoeitin receptor agonists (eltrombopag) averages 10 to 15 days; thus, they are unlikely to replace steroids or IVIG. Severe ITP with platelet counts <5000/µL is associated with fatal hemorrhages in the brain and internal organs. Elderly patients, those with refractory disease or a previous history of hemorrhage, and patients with concomitant bleeding disorders (hemophilia, uremia) are at higher risk for life-threatening hemorrhage.6
Drug-induced thrombocytopenia. In DIT, drug-dependent antibodies against platelet glycoprotein epitopes form, induce the immune-mediated destruction of platelets, and impair thrombopoiesis. DIT is a misnomer because the “drug” may be a prescribed or over-the-counter medication, herb, food, beverage, or other substance (eg, walnuts, cow’s milk, cranberry juice, tonic water).1,11 This exposure variability can make it difficult to distinguish DIT from ITP. A database of DIT associations can be found at https://www.ouhsc.edu/platelets/ditp.html. Patients usually present with moderate to severe thrombocytopenia (<50,000/μL) and associated bleeding manifestations (Table 1). DIT usually occurs within 2 to 3 days (sometimes within hours) after a previously taken drug has been taken or within 1 to 2 weeks of daily exposure to a new drug. Once the drug is discontinued, thrombocytopenia resolves in 5 to 10 days. In patients exposed to a single drug and with no other explanation for thrombocytopenia, recovery after drug discontinuation provides empiric evidence of DIT; recurrent thrombocytopenia following re-exposure to the drug is confirmatory. Recurrent, symptomatic thrombocytopenia with recovery within days, even in the absence of specific treatment, should prompt investigation of DIT.1 Many laboratory methods can detect the presence of drug-dependent antiplatelet antibodies.
Heparin-induced thrombocytopenia (HIT), a special case of DIT, is a clinical emergency that occurs in 0.5% to 5% of heparin-treated patients and approximately 1 in 5000 hospitalized patients. HIT accounts for <1% of cases of thrombocytopenia in the ICU.1,12 In HIT, IgG antibodies form a complex with platelet factor 4 to activate platelets, alter endothelial cells, and increase thrombin generation. Although ITP and usually DIT may lead to bleeding complications, HIT paradoxically induces a hypercoagulable state. Early identification is paramount because thromboembolic complications develop in about 50% of cases, most commonly deep vein thrombosis and pulmonary embolus.12 HIT should be suspected in any patient who while on heparin therapy has a >50% decrease in the platelet count from baseline, particularly if the onset is 5 to 10 days after exposure or if hypercoagulability develops. Thrombocytopenia is usually moderate, with median platelets counts at 50,000 to 80,000/µL and nadir counts rarely <20,000/µL.1,13 Two risks for HIT include the administration of unfractionated heparin rather than low-molecular-weight heparin (LMWH; incidence of HIT is 10 times higher12) and the administration of heparin during or after major surgery. In about 30% of cases, HIT has an acute onset.1 These patients usually received heparin within the previous 3 months and may have circulating platelet factor 4 antibodies. Pre-existing antibodies may also cause anaphylactoid reactions within 30 minutes of the intravenous bolus. Clinicians should review platelet counts on days 5, 7, and 9 following the initiation of heparin or following major surgery while the patient is on heparin to monitor for HIT. Notably, up to 20% of cases of thrombosis occur before or during the drop in the platelet count and may not be preventable.12 Clinicians can use clinical scoring systems such as the 4 T’s: thrombocytopenia, thrombosis (venous and arterial thrombosis, necrotic skin lesions at heparin injection sites), timing, and exclusion of other causes of thrombocytopenia to estimate the probability of HIT. Patients with intermediate- or high-probability scores should discontinue heparin and start argatroban, the direct thrombin inhibitor approved for the treatment of HIT.12 Duplex ultrasound can be used to evaluate for deep venous thrombosis, and platelet factor 4–heparin IgG immunoassays aid in confirmation.
Thrombotic thrombocytopenic purpura. Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disorder in which platelet microthrombi occlude the microvasculature, causing ischemia in the brain, kidneys, heart, and other organs. TTP is initiated by ultra-large precursors of von Willebrand protein that are usually cleaved to normal size by plasma enzyme ADAMTS13. Inhibition of this enzyme by an autoantibody or toxin accounts for acquired forms of TTP, whereas chronic or recurrent episodes suggest a congenital deficiency. The ultra-large hyperactive multimers remain attached to the endothelial cell surface and induce platelet aggregation and consumption. Platelet and hyaline thrombi with complete or partial blood vessel occlusion are the histopathologic finding.14 The incidence of TTP is greater in black female patients,14 and the peak incidence is in the fourth decade. The mnemonic for the classic pentad of TTP clinical manifestations is FART’N: fever, anemia, renal failure, thrombocytopenia, and neurologic dysfunction; however, only 20% to 30% of patients have the complete pentad. The most common presentation is petechiae with fluctuating neurologic symptoms.6 Fever is present in 50% of patients, and 10% to 40% report “flulike symptoms” in the preceding weeks.14 TTP must be considered in cases of thrombocytopenia and microangiopathic hemolytic anemia alone. Neurologic dysfunction may present as fluctuating levels of consciousness, altered mental status, headache, seizures, paresthesias, hemiplegia, visual changes, aphasia, dysarthria, and/or coma (Table 4).
A critical step in the assessment of TTP is to rule out other consumptive coagulopathies, such as disseminated intravascular coagulation (DIC). Fibrinogen degradation products are elevated in 50% of patients with TTP.14 In TTP, the normal values for D-dimer, fibrinogen, parameters of liver function, PT, and PTT help to distinguish it from DIC. Baseline laboratory tests should be ordered, but treatment with plasma exchange should be initiated as soon as possible, before the results are obtained and preferably within 4 to 8 hours.15 Severely reduced ADAMTS13 activity (<5%) with or without an inhibitor or antibody confirms the TTP diagnosis and has a specificity of 90% in distinguishing acute TTP from hemolytic uremic syndrome (HUS). Measurement of ADAMTS13 is necessary in the workup for TTP but is not a diagnostic criterion because the levels may be normal in patients who otherwise have all the features of TTP.14 Elevated levels of troponin T are seen in 50% of cases of acute idiopathic TTP and are a poor prognostic indicator because coronary artery occlusion is a frequent cause of early death.15
TTP is a medical emergency; the untreated mortality rate of 90% can be reduced to 10% to 20% with prompt plasma exchange (PEX; 3-5 L/d). PEX removes antibodies and replenishes normal plasma proteins. Early death still occurs, in half of these cases within 24 hours of presentation, primarily in women.15 It is critical to differentiate TTP from other causes of thrombocytopenia early because platelet transfusions, which may increase the risk for vascular micro-occlusion, are contraindicated (unless life-threatening bleeding is present). The incidence of symptomatic heart failure is increased in patients who have received a recent platelet transfusion.15 Fresh frozen plasma can be initiated if there is any delay in PEX; however, PEX is preferred because a larger amount of plasma can be given without fluid overload. Packed red blood cells and oral folic acid can be given to correct anemia. Immediately after PEX, adjunct corticosteroids are administered. Daily PEX is continued until the platelet count and LDH level are normal for a minimum of 2 days after complete remission (platelet count >150,000/µL).15 Rituximab is increasingly being used as a first-line agent for acute TTP and is preferred for patients with neurologic or cardiac involvement15; early administration is associated with faster remission and fewer cycles of PEX.6 Once the platelet count is >50,000/µL, initiate LMWH thromboprophylaxis.15 Patients with frequent relapses of TTP are candidates for splenectomy.
Hemolytic uremic syndrome. HUS is a major thrombotic microangiopathy characterized by signs of microangiopathic hemolysis (as in TTP), thrombocytopenia, and variable manifestations of organ involvement. Clinically and pathologically, TTP and HUS overlap, but these entities are distinctly different in pathogenesis. Severe deficiency of ADAMTS13 is the hallmark of TTP but is not seen in HUS. Additionally, the severe thrombocytopenia of TTP is not present in HUS, in which ADAMTS13 levels are >5% to 10%.16 Most commonly, HUS is associated with diarrhea due to enteric infection with Shiga toxin–producing Escherichia coli 0157:H7 (STEC-HUS, the most common serotype) or Shigella species. These pathogens are potent activators of the alternative complement pathway. STEC-HUS is the most common cause of acute renal failure in children and accounts for 90% of all cases of HUS in this population.17 In North America, the incidence is highest in children 1 to 5 years of age: 6.1/100,000 in children <5 years vs 2/100,000 in adults.16,17 Cattle and sheep are the main reservoirs, and the major mode of transmission is the ingestion of food contaminated with animal feces. After a 3- to 8-day incubation period, watery or bloody diarrhea, nausea, vomiting, and fever may occur. The risk for the development of HUS after bloody diarrhea due to E. coli infection is about 15%.17 Factors associated with HUS evolution include the use of anti-motility agents and antibiotics, bloody diarrhea, leukocytosis, young age, and female gender.17 There is also a rarer form of infection-related HUS that is caused by disseminated Streptococcus pneumoniae, often associated with sepsis, meningitis, or pneumonia. Recovery is often spontaneous, but acute renal failure that lasts about 2 weeks develops in 26% of patients.17 About 80% of patients recover, and STEC-HUS carries a 3% to 5% mortality rate.17
Atypical HUS is due to a chronic deficiency of complement regulatory proteins, particularly factor H, factor I, and thrombomodulin (membrane cofactor protein). The alternative pathway is active in plasma and will cause a minor attack on body tissues unless it is downregulated by these regulatory proteins. Here, the pathway is continuously stimulated by the activation of C3, which leads to a cascade reaction potentiating platelet activation, aggregation, and complement-mediated endothelial cell injury throughout the microvasculature. Atypical HUS accounts for only 5% of all HUS cases, with an incidence of 2/million in adults and 3.3/million in children younger than 18 years; in 70% of pediatric cases, the onset is before age 2 years.16,17 Infection (respiratory or diarrheal) triggers the onset of atypical HUS in 50% of adults and 80% of pediatric cases.17 As such, the presence of diarrhea cannot reliably distinguish STEC-HUS from atypical HUS or TTP because diarrhea occurs in one-third of atypical HUS cases and is not uncommon in TTP. Atypical HUS has a worse outcome than STEC-HUS, with up to 50% of cases progressing to end-stage renal failure within a year and 25% of patients dying during the acute phase.16
The same organs are affected in HUS and TTP, but in HUS the lesions are most numerous in the renal vasculature and there is minimal neurologic dysfunction. Acute kidney injury supports a diagnosis of HUS rather than TTP; acute renal failure affects <5% of patients with TTP at presentation.16 Of note, in 20% of patients with an initial presentation of atypical HUS, although some proteinuria or hematuria may be present, renal function is preserved.16 The lungs are almost never involved in TTP, whereas pulmonary disease is frequent in untreated atypical HUS.16 It is essential to differentiate between these disorders quickly because the PEX that is standard for TTP has no role in HUS. Overall, patients with thrombocytopenia (<150,000/µL or >25% decrease from baseline) plus signs of microangiopathic hemolysis and at least one manifestation of organ damage (neurologic, renal, or gastrointestinal most commonly) should be treated for thrombotic microangiopathy, and time-sensitive PEX should be initiated. Subsequent laboratory analysis will confirm the diagnosis; the detection of toxin-producing bacteria in stool culture or via serology or the presence of an anti-0157 antibody titer supports a diagnosis of STEC-HUS; ADAMTS13 activity <5% to 10% is likely TTP, and if >5% to 10% is likely atypical HUS. Further investigation of atypical HUS includes screening for complement system abnormalities (serum C3 and C4 levels, factor H and factor I levels). As in TTP, platelet transfusions are strongly contraindicated in HUS unless a severe hemorrhagic condition is present. For STEC-HUS, treatment includes (intravenous) fluid hydration, supportive care, and hemodialysis, with renal transplant as needed. Antibiotic therapy is not needed. In atypical HUS, PEX is the first-line treatment per expert opinion, although the efficacy is variable according to mutated factor.17 Eculizumab, a monoclonal anti-C5 antibody, was recently approved for atypical HUS therapy; the data report success in early use as well as in the prevention and treatment of post-transplant recurrence.17 Renal transplant in atypical HUS may not be recommended for patients with certain mutations.
Disseminated intravascular coagulation. In disseminated intravascular coagulation (DIC), an underlying condition leads to the systemic intravascular activation of coagulation; the simultaneous generation of thrombin and fibrin results in thrombosis in small to medium-size vessels. The process culminates in organ ischemia and dysfunction and/or severe bleeding due to platelet and clotting factor consumption. The frequency of DIC in hospitalized patients is about 1.72%.18 The most common association is severe sepsis or septic shock. Clinically overt DIC may occur in 30% to 50% of patients with gram-negative sepsis18 but is estimated to be as common in patients with gram-positive sepsis. Other causes include the following: major trauma, burns, prolonged surgery, massive blood transfusion or ABO-incompatible transfusion, malignancy (especially acute promyelocytic leukemia or non-Hodgkin lymphoma), and obstetric complications (most commonly pre-eclampsia; also retained fetus, amniotic fluid embolism, placental abruption). An increase in tissue factor production and activity is paramount in initiating DIC and is found to be significant in injured tissue and in leukemic cells and solid tumors.18 Other contributors, particularly in cases of septic DIC, include elevated cytokines, elevations of plasminogen activator inhibitor 1, endothelial activation, lipopolysaccharides, histones, and activated leukocytes.
Guidelines highlight four types of DIC based on the predominance of hyperfibrinolysis or hypercoagulation.19 The diagnosis and treatment of these types differ, and clinicians must be aware that types may shift or change. In cases of hyperfibrinolysis, as seen in patients with leukemia, obstetric disease, or aortic aneurysm, bleeding-type DIC develops. In cases ofhypercoagulation, as seen in patients with sepsis, organ failure-type DIC develops. When both hypercoagulation and hyperfibrinolysis have a weak presence, patients may be asymptomatic. However, the strong presence of both factors, as seen in major bleeding after surgery or in obstetric disease, leads to massive bleeding or consumptive-type DIC. Guidelines recommend that DIC be diagnosed with a combination of laboratory markers trended serially rather than a single test. In clinical practice, the diagnosis may be based on the following: an underlying disease associated with DIC, an initial platelet count <100,000/μL or rapidly declining, prolongation of the PT and PTT (>1.5 times the normal value), the presence of fibrin degradation products, and low levels of coagulation inhibitors such as antithrombin III.18 The PT is prolonged in 50% of patients during the clinical course.19 Elevated levels of fibrin degradation products indicate ongoing hyperfibrinolysis together with low levels of plasminogen and α2-antiplasmin. Serial monitoring of fibrin degradation products may be used to evaluate the response to therapy. A decreased fibrinogen level (<1.5 g/dL) is observed in cases of DIC due to leukemia or obstetric disease but is rare in patients with sepsis.19 Levels of major physiologic anticoagulants, such as antithrombin III, protein C, and tissue factor pathway inhibitor, are low in DIC and are associated with increased mortality, particularly in sepsis.18 New assays monitoring thrombin generation and its activation of the protein C and fibrinolytic pathways are also being used to monitor DIC.
It is critical to identify and treat the underlying disorder because DIC commonly spontaneously resolves once the trigger is removed. Otherwise, treatment is individualized according to the hemodynamic status of the patient and the type of DIC. Guidelines recommend platelet transfusion and fresh frozen plasma in patients who have DIC with active bleeding or those at high risk for bleeding, particularly when the platelet count is <50,000/µL.19 Large volumes of plasma (up to 6 units per day) may be required to correct coagulation defects; an initial dose of fresh frozen plasma of 15 mL/kg is clinically recommended. Deficiencies in fibrinogen associated with the massive bleeding type of DIC can be corrected with the administration of purified fibrinogen concentrates or cryoprecipitate. The standard of care in nonbleeding types of DIC is prophylaxis with unfractionated heparin or LMWH and/or mechanical methods. Small studies suggest that LMWH is superior to unfractionated heparin for treating DIC because it has at least the same antithrombotic potential with a decreased risk for bleeding.18,19 Heparin mitigates the high risk for venous thromboembolism in DIC and has the benefit of partially inhibiting the activation of coagulation. It is particularly useful in those with clinically overt venous thromboembolism or extensive fibrin deposition evidenced by acral ischemia.18,19 Clinical studies have not shown that heparin treatment significantly increases the incidence of bleeding, but it is not recommended in patients with the bleeding type of DIC.18,19 In studies of DIC in patients with severe sepsis, the 28-day mortality was lower in the heparin-treated group than in the placebo group.19 Particularly in cases of sepsis-related DIC, the administration of antithrombin III and activated protein C concentrates, which have anticoagulant and anti-inflammatory effects, has been shown benefit in reducing DIC and mortality and improving organ function.18
Considerations for pregnant patients
Platelet counts <150,000/µL are seen in 6% to 15% of women at the end of pregnancy, and counts <100,000/µL are observed in 1%.1 These counts are most commonly gestational thrombocytopenia (70% of cases, mild in an otherwise healthy pregnancy); other causes are pre-eclampsia (21%) and ITP (3%)1. Gestational thrombocytopenia is observed in the mid-second to third trimester of pregnancy and is an extreme variation of the physiologic decrease in platelets normally observed; counts <70,000/µL are rare,1,2 and gestational thrombocytopenia requires no change from routine obstetric care.
If there is no past history of thrombocytopenia except in a former pregnancy, the thrombocytopenia should resolve spontaneously within 1 to 2 months after delivery with no sequelae or thrombocytopenia in the newborn. ITP occurs in 1/1000 to 2/1000 pregnancies but is the most common cause of isolated thrombocytopenia in the first and early second trimesters.1 One-third of cases are diagnosed during pregnancy, whereas two-thirds of patients report pre-existing disease.1 In ITP, IgG autoantibodies may cross the placenta and cause severe neonatal thrombocytopenia in 9% to 15% of cases.1 A platelet count <50,000/µL in pregnancy should be diagnosed as ITP.
No laboratory parameter predicts the platelet count in the fetus. Pregnant women with platelet counts >30,000/μL without bleeding do not require any treatment until week 36 of gestation unless delivery is imminent.10 First-line management of ITP does not change during pregnancy. Steroids or IVIG is recommended, and these have relatively few fetal complications; oral prednisone and prednisolone cross the placenta at a lower rate than dexamethasone. Refractory ITP in pregnancy is treated with combination steroid/IVIG or splenectomy, although splenectomy should be avoided if possible. A platelet count >50,000 /µL is usually sufficient for cesarean delivery.6 Pregnant patients with vWD usually have no problems during pregnancy but may be at risk for postpartum hemorrhage, even with treatment, because vWF and factor VIII activity decrease after childbirth.6 Severe thrombocytopenia or associated hypertension, renal insufficiency, and/or microangiopathic hemolytic anemia should prompt an evaluation for a more serious obstetric condition, such as pre-eclampsia, TTP, or HELPP (hemolysis, elevated liver enzymes, low platelet count) syndrome.
The evaluation of most disorders of primary hemostasis begins with a focused history and physical examination, complete blood cell count with platelet trend, and examination of the peripheral smear. The most common conditions encountered include ITP and DIT, but clinicians must be aware of the extensive differential diagnosis if they are to determine the relevance of the platelet count as well as the patient’s risk for bleeding, thrombosis, and other complications.
Danielle Kruger, PA-C, MSEd, is an associate professor in the Physician Assistant, Bachelor of Science program at St. John’s University College of Pharmacy and Health Sciences, and a physician assistant practicing emergency medicine, and Director of Physician Assistant Development at Coney Island Hospital in Brooklyn, NY.
- Stasi R. How to approach thrombocytopenia. Hematology Am Soc Hematol Educ Program. 2012;2012:191-197.
- George JN, Arnold DM. Approach to the adult with unexplained thrombocytopenia. UpToDate. https://www.uptodate.com/contents/approach-to-the-adult-with-unexplained-thrombocytopenia. Updated October 19, 2017. Accessed October 26, 2017.
- Bowman M, Mundell G, Grabell J, et al. Generation and validation of the Condensed MCMDM1-VWD Bleeding Questionnaire for von Willebrand disease. J Thromb Haemost. 2008;6:2062-2066.
- Ballas M, Kraut EH. Bleeding and bruising: a diagnostic work-up. Am Fam Physician. 2008;77:1117-1124.
- American Society of Hematology. 2012* clinical practice guidelines on the evaluation and management of von Willebrand disease (VWD). http://www.hematology.org/Clinicians/Guidelines-Quality/Quick-Reference.aspx#a3. Accessed October 26, 2017.
- Thiagarajan P. Platelet disorders: overview of platelet disorders. Medscape.http://emedicine.medscape.com/article/201722-overview. Updated August 5, 2017. Accessed October 26, 2017.
- Mohanty D, Shetty S. Von Willebrand Disease: an update. J Blood Disorders Transf. 2014;5:238. doi:10.4172/2155-9864.1000238
- Simon D, Kunicki T, Nugent D. Platelet function defects. Hemophilia. 2008;14:1240-1249.
- Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117(16):4190-4207.
- Kessler CM. Immune thrombocytopenic purpura (ITP). Medscape. www.emedicine.medscape.com/article/202158-overview. Updated December 2, 2016. Accessed October 26, 2017.
- Visentin GP, Liu CY. Drug-induced thrombocytopenia. Hematol Oncol Clin North Am. 2007;21:685-696.
- Solomon CG. Heparin-induced thrombocytopenia. N Engl J Med. 2015;373:252-261.
- Cuker A, Crowther M. 2013 Clinical practice guideline on the evaluation and management of adults with suspected heparin-induced thrombocytopenia (HIT). American Society of Hematology. Accessed October 26, 2017.
- Saifan C, Nasr R, Mehta S, Acharya PS, El Sayegh S. Thrombotic thrombocytopenic purpura. J Blood Disord Transfus. 2012;S3:001. doi:10.4172/2155- 9864.S3-001
- Scully M, Hunt B, Benjamin S, et al; British Committee for Standards in Haematology. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol. 2012;158:323-325. doi:10.1111/j.1365-2141.2012.09167.x
- Laurence J. Atypical hemolytic uremic syndrome (aHUS): making the diagnosis. Clin Adv Hematol Oncol. 2012;10(10 Suppl 17):1-12.
- Salvadori M, Bertoni E. Update on hemolytic uremic syndrome: diagnostic and therapeutic recommendations. World J Nephrol. 2013;2:56-76.
- Dalainas I. Pathogenesis, diagnosis and management of disseminated intravascular coagulation: a literature review. Eur Rev Med Pharmacol Sci. 2008;12:19-31.
- Wada H, Matsumoto T, Yamashita Y. Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines. J Intensive Care. 2014,2:15.