Diagnosis and Management of Prothrombotic Disorders in the Intensive Care Unit

Diagnosis and Management of Prothrombotic Disorders in the Intensive Care Unit

Ashkan Emadi

Michael B. Streiff


Arterial and venous thromboembolism are among the most common causes of hospitalization in the United States [1,2]. Given the severity of illness of patients in the intensive care unit (ICU), critical care physicians are likely to manage patients with prothrombotic conditions. In this chapter, we will review the regulation of normal hemostasis (which is required to prevent excessive activity of platelets and/or coagulation factors) and the biology, diagnosis and management of selected prothrombotic disorders in the critical care setting.

Prophylaxis and the general approach to treatment of venous thromboembolism (VTE) are discussed in Chapter 52, “Venous Thromboembolism: Pulmonary Embolism and Deep Venous Thrombosis.”

Regulation of Normal Hemostasis

Hemostasis maintains the integrity of the closed circulatory system after vascular injury. A tenuous balance of prothrombotic (i.e., platelets, coagulation proteins) and endogenous antithrombotic (i.e., antithrombin, nitric oxide) mechanisms ensures hemostasis without pathologic thrombosis. Disruptions of this balance are common in critically ill patients and can lead to clinically significant bleeding or thrombosis. Additional information regarding the normal control of bleeding is present in Chapter 108, “Disorders of Hemostasis in Critically Ill Patients.”

The potentially prothrombotic activity of coagulation factors and platelets, however, is opposed by negative regulators of hemostasis. Platelet activation is inhibited by endothelial-derived nitric oxide, prostacyclin, and the ectonucleotidase CD39, which together antagonize platelet activation. The tissue factor pathway is inhibited by tissue factor pathway inhibitor (TFPI). TFPI is synthesized by the endothelium and binds to factor Xa and inhibits its function as well as the activation of factor X by the tissue factor/factor VIIa complex. Since its concentrations increase dramatically with heparin administration, TFPI probably contributes to the antithrombotic efficacy of unfractionated and low-molecular-weight heparin (LMWH) [3,4].

Antithrombin (AT) (formerly antithrombin III) is a liver-derived serine protease inhibitor that inhibits factors XIIa, XIa, IXa, and, in particular, Xa and thrombin by binding to their active sites. Heparin accelerates this reaction to several thousandfold, thus explaining its potent anticoagulant activity. Protein C (PC) is a liver-derived, vitamin K–dependent protease that is activated on the surface of intact endothelium by thrombin bound to thrombomodulin. This activation event is enhanced by the presence of endothelial PC receptor. Activated protein C (APC) when complexed with its cofactor, protein S (PS), on phospholipid-rich surfaces catalyzes the inactivation of activated forms of factors V and VIII (also known as factor Va and factor VIIIa). PS is a liver-derived, vitamin K–dependent protein that binds to the APC and accelerates its inactivation of factors Va and VIIIa. It exists in the plasma in an active free form that can complex with PC and an inactive form bound to C4b-binding protein [5].

Further regulation of the coagulation cascade is provided by the fibrinolytic system, whose components include plasminogen, tissue plasminogen activator (TPA), plasminogen activator inhibitor I and II, α2-antiplasmin, and thrombin activatable fibrinolysis inhibitor (TAFI). Plasminogen is a liver-synthesized plasma protein that is converted to plasmin on activation by TPA. Plasmin cleaves fibrin and is principally responsible for clot dissolution and remodeling in the intravascular compartment. Activation of plasminogen is opposed by plasminogen activator inhibitors I and II which inhibit TPA from activating plasminogen. α2-Antiplasmin is synthesized in the liver and binds to plasmin and prevents it from digesting fibrin clot. TAFI is a carboxypeptidase that is activated by the thrombin–thrombomodulin complex. It removes C-terminal lysine residues from partially digested fibrin clot, thereby downregulating the binding of additional plasminogen to the fibrin clot and thus slowing fibrinolysis [6].

Thrombophilic Disorders

Thrombophilic disorders are inherited or acquired conditions that variably increase the risk of venous or arterial thromboembolism depending on the particular alteration and the severity of its impact on the hemostatic mechanism. From a practical diagnostic standpoint, it is most useful to divide these disorders into conditions that are associated with venous or arterial thromboembolism (Table 111.1). A more detailed description of each thrombophilic state follows below along with the appropriate approach to diagnosis.

Factor V Leiden

Factor V Leiden (FVL) is the most common inherited thrombophilic condition affecting approximately 5% of Caucasian European Americans, 2% of Hispanic Americans, 1% of African Americans and Native Americans, and 0.5% of Asian Americans [7]. FVL refers to a single base change (Arg506Gln) in the factor V gene (G1691A) that eliminates the first and most important of three APC cleavage sites. The mutation slows down the inactivation of factor Va by APC leading to more thrombin generation. FVL heterozygosity is associated
with a 5-fold increased risk of VTE, whereas homozygosity increases this risk by at least 10-fold [8]. FVL does not appear to be associated with an increased risk of arterial thromboembolism [9]. FVL heterozygosity and homozygosity increase the risk of recurrent VTE modestly by 1.56-fold (95% confidence interval [CI], 1.14 to 2.12) and 2.65-fold (95% CI, 1.18 to 5.97), respectively [10]. Diagnosis of FVL relies on a functional screening assay, the APC resistance assay, and confirmatory DNA-based testing.

Table 111.1 Inherited and Acquired Prothrombotic Conditions

Venous thromboembolism Arterial thromboembolism
   Factor V Leiden
   Prothrombin gene mutation
   Antithrombin (III) deficiency
   Protein C deficiency
   Protein S deficiency
   Elevated factor VIII activity
   Elevated factor IX level
   Elevated factor XI level
   Antiphospholipid syndrome
   Heparin-induced thrombocytopenia
   Central venous catheters
   Vena cava filters
   Cardiopulmonary failure
   Exogenous estrogens
   Antiphospholipid syndrome
   Heparin-induced thrombocytopenia

The Prothrombin G20210A Mutation

The prothrombin gene mutation G20210A (PGM) is present in 1.1% of non-Hispanic Whites and Mexican Americans and in 0.3% of African Americans [11]. It is associated with a 30% increase in prothrombin levels in heterozygotes resulting in a 2.8-fold increased risk of VTE [12]. Homozygosity for the FII mutation is rare, so reliable risk estimates are not available. The PGM does not appear to increase the risk of arterial thromboembolism or recurrent VTE [10,13]. Diagnosis of the PGM is based on DNA testing of peripheral blood.

Compound Heterozygotes for the FVL and FII Mutations

Given the relatively high frequency of FVL and the PGM in the population, double heterozygotes for these mutations are occasionally identified. Compound heterozygosity for both FVL and the PGM is associated with a 20-fold increased risk for first-ever VTE and a 4.8-fold risk for recurrent VTE (95% CI, 0.50 to 46.3) [8,10].

Protein C Deficiency

PC is an important endogenous anticoagulant protein that inactivates factors Va and VIIIa. Heterozygous PC deficiency affects 0.2% of the general population and 3.2% of unselected patients with their first episode of VTE [14]. It is associated with a sevenfold increased risk of VTE [15,16]. Homozygous PC deficiency is a rare thrombophilic syndrome that produces life-threatening thrombotic complications shortly after birth, a condition called neonatal purpura fulminans. PC deficiency may result from mutations that produce quantitative (type I deficiency) or qualitative (type II) defects. Therefore, accurate diagnostic testing should include both PC activity and antigen levels. Acquired causes of PC deficiency include disseminated intravascular coagulation/acute thrombosis, vitamin K deficiency, vitamin K antagonist (VKA) therapy (i.e., warfarin), and liver disease. Therefore, diagnostic testing should be performed in the absence of these conditions to ensure that laboratory results are interpretable [17].

Protein S Deficiency

PS is the nonenzymatic cofactor for activated PC. PS circulates in two forms: approximately 60% is bound to C4b binding protein, while the remaining 40% is free. Only free PS has cofactor activity. The incidence of PS deficiency is estimated to be 0.03% to 0.13%. PS deficiency affects 7.3% of unselected patients with venous thrombosis [14,18]. PS deficiency is associated with an eightfold increased risk of VTE [15] and may be a risk factor for arterial thromboembolism [19,20].

Deficiency of PS may by quantitative (type I deficiency) or qualitative (type II). An additional type of deficiency (type III) can be acquired during pregnancy, inflammatory states, and estrogen therapy, which increase C4b binding protein levels leading to reduced free PS. Other acquired causes of PS deficiency include vitamin K deficiency, VKA therapy (i.e., warfarin), acute thrombosis, and liver disease. For accurate diagnosis of PS deficiency, all three tests including PS activity, total PS antigen and free PS antigen should be checked in the absence of conditions associated with acquired PS deficiency [18].

Antithrombin (III) Deficiency

AT inhibits serine protease coagulation factors by binding to the active site of the target protease and forming an inactive complex. Heterozygous type I AT deficiency is rare, affecting 1 in 2,000 in the population. It is associated with an 8- to 10-fold increased risk of thrombosis and is present in 1% to 2% of patients with thrombosis [21]. AT deficiency does not increase the risk of arterial thromboembolism [19,20].

Deficiency of AT may by quantitative (type I deficiency) or qualitative (type II). Complete AT deficiency is incompatible with life. The diagnosis of AT deficiency is made by measuring AT activity and antigen levels. Acquired AT deficiency may occur in acute thrombosis, disseminated intravascular coagulation, and during heparin therapy. Artifactual increases in AT can be seen during therapy with VKAs (e.g., warfarin) [21].


Dysfibrinogenemia is a rare inherited thrombophilic state caused by mutations in the Aα, Bβ, or γ fibrinogen genes and affects fewer than 1% of patients with venous thrombosis. Acquired dysfibrinogenemia is associated with chronic liver disease and cirrhosis as well as liver cancers and renal cell
carcinoma. Approximately one third of cases of dysfibrinogenemia are complicated by thrombosis (venous more commonly than arterial), possibly because of reduced thrombin binding or inhibition of fibrinolysis. Diagnosis of dysfibrinogenemia is made by measuring fibrinogen function (e.g., Clauss fibrinogen assay) as well as fibrinogen antigen. Typically, the fibrinogen activity level is much lower than the fibrinogen antigen level [22,23].


Homocysteine is a thiol-containing amino acid that is converted to methionine by methionine synthase with vitamin B12 and 5-methyltetrahydrofolate as cofactors. Homocysteine is also converted to cysteine by cystathionine β-synthase, which requires pyridoxine (vitamin B6) as a cofactor. Congenital causes of hyperhomocysteinemia include homocystinuria (deficiency of cystathionine β-synthase) and inheritance of the thermolabile mutation in the methylene tetrahydrofolate reductase (MTHFR) gene. Homocystinuria is associated with markedly increased levels of homocysteine (> 100 μmol per L) and developmental delay, arterial and venous thromboembolism, eye abnormalities, and premature coronary artery disease. Thermolabile mutations in MTHFR produce much more modest elevations in homocysteine (15 to 30 μmol per L) in only a minority of cases, and generally in association with folate deficiency. Acquired causes of hyperhomocysteinemia include deficiency of vitamin B12, folate and pyridoxine, and renal insufficiency [24].

Hyperhomocysteinemia has been associated with a 20% increase in cardiovascular disease for each 5 μmol per L increase in fasting homocysteine levels [25]. Homozygosity for the MTHFR mutation is associated with a 1.16-fold increased risk of coronary artery disease [26]. This risk appeared to be significantly modified by folate status. Hyperhomocysteinemia is also associated with a two- to threefold higher risk of initial and recurrent VTE [27,28]. However, randomized studies of vitamin supplementation in patients with venous and arterial thrombotic disease did not demonstrate improved clinical outcomes [29,30,31]. Therefore, the utility of homocysteine lowering therapy is in question. The diagnosis of hyperhomocysteinemia is based on demonstrating elevated levels of homocysteine in a fasting blood sample. Methionine loading prior to sampling can increase the sensitivity of testing.

Elevated Coagulation Factor Levels

Elevated factor VIII (> 95 percentile) has been associated with an increased risk of initial and recurrent VTE [32,33]. Elevated factor VIII levels appear to be inherited, but the responsible genetic alterations have yet to be completely characterized. Factor VIII activity levels are the diagnostic test of choice. This test should be done at least 6 months after an episode of VTE and in the absence of inflammation to avoid spurious elevations. Elevated factor IX and XI antigen levels have been associated with a 2.5- and 2.2-fold increased risk of initial VTE, respectively [34,35].

Acquired Prothrombotic Disorders

Although inherited thrombophilic conditions may lead to thrombosis, the attention paid to their potential presence by physicians and patients alike is often disproportionate, because acquired prothrombotic disorders are much more common and, in many cases, more potent causes of thromboembolism. A list of inherited and acquired prothrombotic disorders is displayed in Table 111.1. In this section, we will review several important acquired thrombotic disorders of relevance to the intensive care.


Patients with cancer are at four- to sevenfold increased risk of thromboembolism (venous and arterial) compared with patients without cancer [36,37]. The risks of thromboembolism are influenced by the primary site of cancer, its histology, and stage as well as our treatments for cancer including surgery, chemotherapy, and growth factors such as erythropoietic stimulatory agents. High-risk organ sites include pancreas, brain, and stomach, while lung cancer and colon cancer are associated with intermediate risk and breast cancer and prostate cancer are associated with a lower risk. Adenocarcinoma is associated with a higher risk of thromboembolism than squamous cell carcinoma, and metastatic disease is associated with a higher risk than localized disease. Myeloproliferative disorders, in particular polycythemia vera (PV), are associated with an increased risk of thromboembolism that is mediated at least in part by an increased red cell volume. Therefore, it is essential to control erythrocytosis in patients with PV with phlebotomy (see “Hematologic Conditions” section in the chapter and Chapter 113, “Therapeutic Apheresis: Technical Considerations and Indications in Critical Care”). Surgery increases the risk of thromboembolism by 10-fold, whereas chemotherapy further increases the relative risk of thromboembolism by 50% in cancer patients. Erythropoietic stimulatory agents have been noted to be associated with an increased risk of thrombosis when hemoglobin values exceed 12 g per dL [38].

Unlike congenital thrombophilic states, cancer is associated with both arterial and venous thromboembolism. Thromboembolism can be the first clue to the presence of an occult malignancy. Idiopathic events are 4.8-fold more commonly associated with the presence of occult malignancy than triggered episodes of thromboembolism. The risk of occult malignancy in patients with thromboembolism declines to the background rate in the population over 6 months [39]. Although an randomized clinical trial (RCT) was unable to identify a survival benefit with extensive cancer screening in patients with idiopathic VTE [40], we think it is worthwhile to ensure that patients are up-to-date with preventive healthcare cancer screening (colonoscopy, etc.) and consider computed tomographic scanning to identify occult primaries in patients aged 50 or older presenting with idiopathic VTE.

Cancer patients are also two- to threefold more likely to suffer recurrent VTE and bleeding during therapy [41]. LMWH has been shown to reduce the incidence of recurrent VTE by 50% in patients with cancer, and therefore LMWH rather than oral VKAs should be considered the agent of choice for long-term management of VTE in cancer patients [42].

Heparin-Induced Thrombocytopenia

Thrombocytopenia affects 20% of patients in the ICU [43]. While the true prevalence of heparin-induced thrombocytopenia (HIT) in the ICU is debatable [44], accurate diagnosis and treatment are essential due to the potential thrombotic and hemorrhagic risks associated with the condition.

HIT is an immune-mediated, prothrombotic disorder caused by heparin-dependent, platelet-activating IgG antibodies directed against platelet factor 4 (PF4) that trigger activation of platelets, endothelial cells, and monocytes resulting in consumptive thrombocytopenia and, in 50% of untreated cases,
venous and/or arterial thromboses. Digital/extremity gangrene is a classic finding. Less commonly, skin reactions/necrosis at heparin injection sites or acute systemic reactions (fever, hypotension) occur after heparin administration. Surgical patients (particularly, orthopedic and cardiothoracic) are at high risk for HIT, while medical patients are at intermediate risk and obstetric and pediatric patients are at low risk [45,46]. The clinical probability of HIT can be assessed using the “4 T score,” a validated, clinical prediction rule (see Chapter 109 for the elements of the 4 T score) [47]. Management of any patient in whom HIT is being seriously considered requires elimination of exposure to all forms of heparin, and prompt initiation of anticoagulation with a direct thrombin inhibitor (see Chapter 109, “Thrombocytopenia and Platelet Dysfunction”). The clinical diagnosis of HIT should be confirmed with objective laboratory testing, such as the widely available enzyme-linked immunosorbent assay (ELISA assay) for heparin-PF4 antibodies. Patients who develop HIT without thrombosis are typically treated with anticoagulation for 1 to 3 months, whereas patients with thrombosis should be at least 3 to 6 months or longer with warfarin as dictated by the thrombotic event. Without treatment, the mortality of HIT is as high as 20% to 25% with a similar percentage of patients surviving with major complications (e.g., stroke or limb loss). Early diagnosis and treatment has improved mortality and morbidity to 5% to 10% [45,46]. Additional information regarding the pathophysiology and management of HIT is discussed in Chapter 109, “Thrombocytopenia and Platelet Dysfunction.”

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Sep 5, 2016 | Posted by in CRITICAL CARE | Comments Off on Diagnosis and Management of Prothrombotic Disorders in the Intensive Care Unit
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