Overview of Complex Thrombohemorrhagic Disorders

Theodore E. Warkentin

Victor J. Marder

This overview of “complex thrombohemorrhagic disorders” emphasizes their heterogeneous clinical presentation ranging from bleeding to microvascular and macrovascular thrombosis (see Table 97.1). These conditions have in common the potential for clinical presentation without symptoms, with bleeding or thrombotic events, or with simultaneous manifestations of hemorrhage, vascular occlusion, and organ failure. Although this disparate group of disorders has varied and distinct etiologies, they nevertheless can mimic one another. For example, a patient who presents with splenic infarction could have an underlying myeloproliferative neoplasm (MPN) or infective endocarditis with splenic artery septic emboli. The former diagnosis is suggested by an elevated platelet count, whereas thrombocytopenia suggests sepsis. Consider also the patient with dyspnea and thrombocytopenia beginning 10 days after cardiac surgery for whom the differential diagnosis includes pulmonary embolism (PE) with or without heparin-induced thrombocytopenia (HIT) and acute sepsis. The diagnosis would be clarified once results of blood cultures, radiologic imaging, and serologic testing for HIT antibodies are available.

To add further complexity, these disorders may coexist. For example, patients with antiphospholipid syndrome (APS) occasionally develop thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS).¹ Acral (distal extremity) limb necrosis may develop in a patient with HIT and deep vein thrombosis (DVT) who is treated with warfarin and thereby develops a variant of coumarin necrosis, venous limb gangrene.² Or, consider the occurrence of HIT with a platelet count nadir of 633 × 10⁹/L that nonetheless represented a substantial decline from the baseline level of 1,235 × 10⁹/L because of preexisting essential thrombocytosis (ET).³

The experienced clinician acquires a “feel” for the subtle differences in clinicopathologic profile among these disorders. For example, in TTP-HUS, the presence of red cell fragments (schistocytes), thrombocytopenia, and elevated lactate dehydrogenase is usually much more marked than in a patient with disseminated intravascular coagulation (DIC) associated with acute sepsis. Although patients with HIT can have red cell fragments too,⁴ this is usually present only in the subgroup with more severe thrombocytopenia and overt (decompensated) DIC. Therefore, careful correlation of the laboratory and clinical picture usually points to the correct diagnosis.

CONSUMPTIVE THROMBOHEMORRHAGIC DISORDERS

The term “consumptive coagulopathy,” or the common term, DIC, does not denote a discrete diagnosis but rather a heterogeneous group of disorders that have in common increased consumption of coagulation factors and/or platelets.⁵ Indeed, some of the entities discussed as separate chapters (e.g., sepsis, TTP-HUS, HIT) represent forms of consumptive coagulopathy. Therefore, consumptive coagulopathies (as with anemia) must not be regarded as a diagnosis but rather as a clinicopathologic syndrome that begs the question, “what is the underlying diagnosis?”

Systemic activation of hemostasis in pathologic settings can have a wide spectrum of clinical consequences, ranging from no clinical effect, to generalized hemorrhage, to widespread microvascular thrombosis that predisposes to multisystem organ dysfunction and acral necrosis. Bleeding tends to predominate in DIC triggered by trauma, obstetrical complications, or snakebites, whereas DIC caused by HIT or metastatic adenocarcinoma tends to produce macrovascular thrombosis affecting large veins and arteries. Some malignancies, however, produce severe bleeding, such as prostate cancer with DIC and/or hyperfibrinolysis. Microvascular thrombosis often accompanies sepsis, particularly when caused by certain organisms (meningococcus, Capnocytophaga canimorsus) that predispose to acral limb necrosis (sepsis-associated purpura fulminans). Contributing causes of thrombosis include severe depletion of protein C and antithrombin, ongoing thrombin production, and reduced limb perfusion secondary to shock or vasopressors.⁶ To further complicate the myriad clinical features, consumption may be restricted to local processes alone, such as with a vascular malformation, aortic aneurysm, or placental abruption, any of which can cause localized activation of coagulation sufficient to deplete platelets and/or coagulation factors.⁷

THROMBOTIC THROMBOCYTOPENIC PURPURA-HEMOLYTIC UREMIC SYNDROME

The duo of microangiopathic hemolysis (red cell fragmentation) and thrombocytopenia—also known as thrombotic microangiopathy, or TMA—in the absence of an alternative explanation constitutes the modern notion of TTP-HUS.⁸^,⁹ Many, if not most, patients with “idiopathic” TTP-HUS have autoantibodies that inhibit function of ADAMTS13 (a disintegrin and

metalloprotease with thrombospondin 1—like domains). Because ADAMTS13 proteolyzes large multimers of von Willebrand factor (vWF) under high shear stress, reduced enzyme activity predisposes patients to formation of platelet-vWF microaggregates in small arterioles (hyaline thrombi) that constitute the pathologic hallmark of TTP-HUS. Associated organ dysfunction can cause neurologic abnormalities, oliguric renal insufficiency, myocardial ischemia, and pancreatitis. The importance of recognizing TTP HUS relates to its special treatment by plasma exchange with fresh frozen (or cryosupernatant) plasma. This therapy reduces mortality, from >90% as occurred before 1964 to <20% today.¹⁰ Illnesses strongly resembling TTP-HUS occur with drugs (e.g., quinine, mitomycin, cyclosporine), hematopoietic stem cell transplantation, pregnancy and the postpartum period, and autoimmune disorders (e.g., systemic lupus erythematosus, APS, acute scleroderma). Sometimes, TTP begins after surgery (“postoperative TTP”), a clinical scenario that could mimic sepsis or HIT.

Table 97.1 Bleeding and thrombosis of complex thrombohemorrhagic syndromes

Disorder	Bleeding	Microthrombosis	Macrothrombosis
Consumptive coagulopathies (DIC)	Variable, depending on cause	Variable, cerebral (mental status), renal (oliguria), skin (purpura fulminans); limb necrosis (acquired protein C depletion)	Variable, large vein and artery thrombosis with underlying adenocarcinoma or HIT, or with use of antifibrinolytic therapy
TTP-HUS	Usually no bleeding, but petechiae and ecchymoses possible with severe thrombocytopenia	Organ dysfunction (CNS, renal) due to arterial platelet-vWF microaggregates	Occasional cerebral artery (thrombotic stroke in children with congenital form)
Vasculitides	Gl bleeding (if vasculitis involves Gl tract, e.g., polyarteritis nodosa); dermal hemorrhage (small-vessel vasculitis); hemoptysis (pulmonary capillaritis)	Variable, “palpable purpura” is a feature of small-vessel vasculitis; renal, neurologic, and other organ dysfunction	Macrothrombosis can be mimicked by nonthrombotic vasculitis—related vessel obstruction (e.g., intimal hyperplasia in giant cell arteritis) or large-artery dissection; aneurysmrelated thrombosis
APS	Bleeding uncommon; when present, usually results from associated thrombocytopenia, low factor II, or anticoagulant therapy	Microvascular thrombosis and multiple organ failure in severe cases	Venous thrombosis in unusual sites (upper limb, abdominal, renal, cerebral), PE, coronary artery, cerebral artery (stroke, TlA), retinal ischemia, nonbacterial endocarditis; hemorrhagic adrenal infarction; recurrent fetal loss (placental infarcts)
MPN	Mucocutaneous, CNS, retinal, retroperitoneal, deep tissue, postoperative, aspirininduced	PV and ET: intracranial (headache, visual disturbances), digital ischemia, erythromelalgia	PV and ET: cerebral artery (transient ischemia or thrombotic stroke), retinal vein occlusion, cerebral sinus thrombosis, coronary (acute Ml, coronary syndromes), DVT, PE, mesenteric/portal/hepatic vein thrombosis
Stem cell transplant	Mucocutaneous bleeding with severe thrombocytopenia; diffuse alveolar hemorrhage; hemorrhagic cystitis	Hepatic veno-occlusive disease; TMA	Venous thromboembolism (DVT, PE)
Sepsis	Bleeding associated with thrombocytopenia, elevated PT or aPTT	Variable, organ dysfunction and dermal/acral necrosis	Uncommon; if DVT present, predisposes to peripheral limb ischemia/necrosis
HIT	Bleeding uncommon, except during anticoagulant therapy	Usually associated with coumarin; rarely, overt consumptive coagulopathy	DVT and PE, cerebral vein thrombosis, limb artery thrombosis, cerebral (stroke), coronary (acute Ml), hemorrhagic adrenal infarction
Coumarininduced necrosis	Early skin necrosis may resemble cutaneous hematoma	Thrombosis of subdermal venules (skin necrosis), venous limb gangrene	Associated large vein thrombosis predisposes to subtending microvascular thrombosis and acral limb necrosis
MPN, myeloproliferative neoplasms; CNS, central nervous system; PV, polycythemia vera; ET, essential thrombocytosis; DVT, deep vein thrombosis; CI, gastrointestinal; Ml, myocardial infarction; PE, pulmonary embolism; DIC, disseminated intravascular coagulation; HIT, heparin-induced thrombocytopenia; PT, prothrombin time; aPTT, activated partial thromboplastin time; TTP-HUS, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome; vWF, von Willebrand factor; APS, antiphospholipid syndrome; TIA, transient ischemic attack.

Classic HUS refers to a disorder in which oliguric renal failure is predominant, although 15% to 25% of patients develop neurologic abnormalities. HUS usually follows a hemorrhagic colitis that most often is caused by Shiga toxin-producing Escherichia coli O157:H7.¹² In 2011, a central European epidemic of Shiga toxin-producing E. coli O104:H4 linked to consumption of sprouts¹³ was associated with a high frequency (20%) of HUS.¹⁴ Treatment of HUS is supportive, although severely affected patients may benefit from plasma exchange or, possibly, immunoadsorption.¹⁵

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