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  1. Disseminated Intravascular Coagulation is defined by the International Society on Thrombosis and Hemostasis as an “acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes.” There are many potential causes of DIC (Table 27.1).
    1. Pathophysiology of DIC is based on the following main mechanisms. First, bacterial exo- and endotoxins (lipopolysaccharide-protein complexes [LPSs]) as well as inflammatory cytokines induce tissue factor expression on circulation monocytes and endothelial cells. This results in a loss of localization of thrombin generation to the site of endothelial injury. Tissue factor expression on monocytes is further enhanced by the surfaces of extracorporeal assist devices such as dialysis, ECMO, and ventricular assist devices (VADs). However, tissue factor expression on monocytes cannot be detected by standard plasmatic coagulation testing but can be by whole-blood viscoelastic testing (ROTEM/TEG). Second, the early phase of DIC is characterized by hypercoagulability (increased clot firmness due to acute-phase reaction with high fibrinogen levels), consumption of physiologic coagulation inhibitors (antithrombin [AT] and protein C), platelet dysfunction, and inhibition of fibrinolysis (upregulation of plasmin activator inhibitor-1 [PAI-1]). This results in thrombosis of the microcirculation and multiple organ failure. Finally, when coagulation factors and fibrinolytic inhibitors are consumed, hypocoagulation and secondary fibrinolysis can result in severe bleeding. Early detection of pathologic thromboelastometric results and platelet dysfunction detected by whole-blood impedance aggregometry on admission at the ICU are associated with worse outcomes.
    2. Clinical features of DIC include hemorrhage from operative or traumatic wounds, oozing from venipuncture sites, petechiae, and ecchymosis. Micro- and macrovascular thrombosis can lead to organ failure.
    3. Diagnosis includes clinical and laboratory data. Recommendations include the use of a DIC scoring system, of which three use different criteria for different types of DIC.
    4. Laboratory tests such as prolonged PT and INR, reduction of platelet counts, and reduced fibrinogen and AT levels may overlap with other coagulopathies. Elevation of fibrin-related markers such as d-dimer, FDPs, and soluble fibrin are common findings not specific to DIC. Peripheral blood smears can reveal schistocytes (fragmented red blood cells [RBCs]), which are formed as RBCs that flow through fibrin strands in the microvasculature are severed. Point-of-care testing includes ROTEM/TEG and aPTT waveforms to support the diagnosis.
    5. Treatment of DIC is aimed at correcting the underlying cause, blood product transfusion when indicated, and pharmacologic treatment. Blood products should be transfused to correct for active bleeding or in preparation for life-saving procedures. Fibrinogen levels should then be corrected to 150 to 200 mg/dL. Platelet transfusion should be considered in patients who are actively bleeding and who have a platelet count of less than 50 000/mm3. However, platelet transfusion should be considered carefully because it may aggravate multiple organ failure and result in secondary bacterial infections. In patients who are not bleeding, the threshold for platelet transfusion should be 10 000 to 20 000/mm3. Other blood components such as FFP and packed red blood cells (pRBCs) should be transfused only in patients with active bleeding or who are at high risk for bleeding. Pharmacologic treatment depends on the type of DIC and includes anticoagulation or antifibrinolytics. The balance of coagulation and fibrinolysis can be further characterized with point-of-care testing (ROTEM/TEG and whole-blood impedance aggregometry) to guide treatment, but hematologic consult should be considered in complicated cases of DIC.
  2. Trauma-Induced Coagulopathy is accepted to be a discrete clinical entity different from DIC (Figure 27.3). In contrast to DIC, hypoperfusion-induced activation of protein C with subsequent cleavage of activated factors V and VIII and downregulation of PAI-1 result in endogenous anticoagulation and primary hyperfibrinolysis. Furthermore, shedding of the endothelial glycocalyx leads to liberation of heparinoids, which intensifies endogenous anticoagulation. In addition, TIC is modulated by hemodilution, hypothermia, and acidosis. TIC is functionally characterized by a reduction in clot strength. With a threshold of clot amplitude at 5 minutes of less than or equal to 35 mm, ROTEM can identify acute traumatic coagulopathy at 5 minutes and predict the need for massive transfusion. Concepts to treat TIC vary widely between the United States and Europe, with some using a fixed transfusion ratio of pRBCs, FFP, and platelets; and others an individualized goal-directed bleeding management using coagulation factor concentrates (fibrinogen and four-factor prothrombin complex concentrate [4F-PCC]) guided by viscoelastic testing (ROTEM/TEG). Randomized clinical trials (RCTs) are missing to show which approach is superior in severe trauma. In traumatic brain injury (TBI), the risk of bleeding and thrombosis is high.
    1. Increasing evidence supports viscoelastic testing for guidance of transfusion in the trauma bay, OR, and ICU setting. Early evidence suggests at least two to three distinct phenotypes of TIC that may be linked to patient characteristics, injury patterns, and comorbidities. TEG allows for distinct characterization of these phenotypes and individualization of therapy. For patients undergoing massive transfusion protocols, RCT evidence has demonstrated that viscoelastic guidance of transfusion improves survival and increases ventilator-free and ICU-free days.
    2. Increased viscoelastic testing has also resulted in the identification of a spectrum of disorders related to fibrinolysis associated with TIC. On the one end of the spectrum, hyperfibrinolysis is common in patients who are severely injured and may warrant the use of antifibrinolytics. Conversely, inhibition of fibrinolysis, or “fibrinolysis shutdown,” has also been observed in patients after an operation and in those with TIC, often resulting in deep vein thrombosis (DVT) and multiorgan failure. Given this complexity, many have argued against blanket administration of antifibrinolytic therapy in exchange for goal-directed therapy for hyperfibrinolysis based on viscoelastic testing. Suggested algorithms can be found in Section III of this chapter.
  3. Mechanical Cardiac Support is increasingly common in patients in critical care and associated with significant complexities in terms of management of coagulopathy both due to devices and critical illness. Beyond the mechanical forces on RBCs, tissue factor expression on monocytes is enhanced by the surfaces of devices such as VADs or ECMO.
    1. Ventricular assist devices may function either as pulsatile or nonpulsatile with anticoagulation varying between differing devices but typically focused on targeting either aPTT 1.5 to 2.5 times normal, an INR 1.5 to 3.5, and/or the use of a low-dose acetylsalicylic acid. Event rates for bleeding and thromboembolic complications in patients with VAD approach 45% and are frequently associated with poor outcomes and high costs. Regarding bleeding, patients with nonpulsatile VADs may develop a similar acquired von Willebrand factor (vWF) syndrome (type 2A), most commonly presenting as gastrointestinal (GI) bleeding, due to the high shear stress induced by the device resulting in cleavage of vWF multimers. This should be managed with antifibrinolytics, desmopressin, factor VIII concentrates, or transfusion. Acquired factor XIII deficiency may also occur because of continuous device-related thrombin generation resulting in factor XIII consumption. Viscoelastic testing is helpful for identification of coagulopathy due to factor XIII deficiency and management. Factor XIII appears to be helpful only when plasma levels are 70% of the normal value. Regarding thromboembolic complications, patients with VADs may experience these events even with aPTT or INR in the therapeutic range given the limitations of these tests. This further emphasizes the need for repeated viscoelastic-guided therapy, including platelet function testing. The detection of heparin-induced thrombocytopenia (HIT) is also complex in patients with VAD given the thrombocytopenia experienced by virtually all patients requiring mechanical support. Although less common in this population, HIT can and should be evaluated as a cause of thrombosis by the use of the 4T score and laboratory workup. Finally, the risk of complications due to allogeneic transfusion (transfusion- related acute lung injury [TRALI], transfusion-associated circulatory overload [TACO], and transfusion-related immunomodulation [TRIM]) is higher in patients with VAD, resulting in many coagulation management algorithms to prioritize fibrinogen and PCCs combined with point- of-care testing. Although this currently exists in the trauma bay and OR, it is likely to make its way to ICUs in the near future.
    2. Extracorporeal membranous oxygenation may also in significant circuit-related thrombosis as well as in vivo bleeding. Etiologies for such coagulopathy are usually attributed to deficiency of factor XIII, thrombocytopenia, acquired vWF syndrome, platelet function defects, hyperfibrinolysis, and intravascular hemolysis. Patients on ECMO are typically anticoagulated with UFH and followed by either aPTT or anti-Xa levels, although DTIs may be used for those with heparin resistance. An ECMO circuit primed only with crystalloid and/or RBCs (without plasma), an initial dilutional thrombocytopenia and coagulopathy often result. Similar to VADs, ECMO circuits result in continuous thrombin formation, thus resulting in fibrinogen consumption, and levels should be monitored and maintained greater than 150, potentially greater than 200 if concerns for bleeding exist. Unexplained bleeding may be attributable to factor XIII deficiency, which should be kept above 70%, and acquired vWF should be managed similarly to the VAD management mentioned earlier. Lastly, intravascular hemolysis often results in renal damage for patients on ECMO. Given that intravascular hemolysis may be an early sign of thrombus formation within the circuit or at the cannula position, free plasma hemoglobin (Hb) should be regularly monitored. Elevated levels are associated with higher mortality, and, when greater than 150 mg/dL, should be managed with therapeutic plasma exchange with FFP as a replacement fluid.
  4. Organ Dysfunction
    1. Liver disease affects coagulation because the majority of factors, except factor VIII and vWF, are produced in the liver. In chronic liver disease, coagulation factors (I, II, V, VII, IX, X, and plasminogen) and inhibitors (AT, protein C and S, α2-antiplasmin, as well as the vWF-cleaving enzyme ADAMTS13) synthesized by the liver, are decreased, whereas the vascular endothelium-derived factor VIII, vWF, tPA, and PAI-1 are elevated. Clinically, this results in a rebalanced hemostasis, although standard plasmatic coagulation tests such as PT and aPTT may be elevated. In fact, thrombin generation assays containing thrombomodulin and viscoelastic tests demonstrate that patients with long-standing liver disease tend to be hypercoagulable. They should be considered for thromboprophylaxis unless contraindicated. Similarly, in acute liver failure, overt bleeding is less common than would be expected because of a “rebalanced” coagulation dysfunction. Thrombocytopenia frequently occurs as the result of splenic sequestration but may be compensated by high vWF levels.
      1. Prophylactic transfusion of FFP and platelets should be avoided, and hemostatic interventions should only be performed in case of clinically relevant bleeding. There is usually response to vitamin K supplementation. Antifibrinolytic drugs or coagulation factor concentrates such as fibrinogen, PCC, or activated recombinant factor VII (rFVIIa) may be appropriate in certain patients. However, the potential benefit of improving hemostasis at the expense of increasing the thrombotic risk should be carefully evaluated in individual patients. Here, viscoelastic testing seems to be helpful to guide therapy in patients with bleeding. Notably, procoagulant agents such as rFVIIa have been shown to improve laboratory values such as PT, without improving control of bleeding during liver transplant or upper GI hemorrhage.
    2. GI dysfunction may result in vitamin K deficiency. Vitamin K, a fat-soluble vitamin, depends on the normal flow of bile and pancreatic exocrine function that is absorbed in the jejunum and ileum and transported via chylomicrons in the lymphatic system. Vitamin K is important in the synthesis of coagulation factors in the liver, including the clotting factors II, VII, IX, and X, as well as the anticoagulant factors protein C and protein S. Vitamin K deficiency is common in prolonged illness and can be repleted 2.5 to 25 mg subcutaneously once or 10 mg subcutaneously daily for 3 days. Vitamin K can be given via an intravenous (IV) line, although both anaphylaxis and subsequent resistance to VKAs thereafter are well documented (eg, a patient who will need to be therapeutically anticoagulated again after temporary reversal). In severe and life-threatening bleeding due to VKAs, for example, in intracerebral hemorrhage or GI bleeding, the effect can be reversed rapidly by the administration of 4F-PCCs. 4F-PCC has been approved by the U.S. Food and Drug Administration (FDA) for this indication since 2013.
    3. Kidney disease may result in uremia and associated platelet dysfunction. The primary therapy is hemodialysis and should be strongly considered before invasive procedures in the event of uremia-related coagulopathy. IV desmopressin as a slow infusion increases multimers of factor VIII: vWF. Cryoprecipitate and treatment of anemia with transfusion of pRBCs in the acute setting can be considered as well. Therapy with less immediate response time includes conjugated estrogens (over the course of 4-7 days) and erythropoietin (over the course of weeks to months).
  5. Postoperative Bleeding, for example, after cardiac surgery or liver transplant, usually is multifactorial. Here, hyperfibrinolysis, fibrinogen deficiency, fibrin polymerization disorders, thrombocytopenia, thrombocytopathy, and impaired thrombin generation can play a major role. Standard plasmatic coagulation tests are limited because of their long turnaround time and their inability to predict bleeding and guide hemostatic therapy in the perioperative setting. Here, ROTEM/TEG as well as point-of-care platelet function analysis have been shown to be superior in reducing transfusion requirements, transfusion-associated adverse events, thromboembolic events, and improving patient outcomes. The use of perioperative bleeding management algorithms guided by ROTEM/TEG is highly recommended here (Figure 27.4). Their clinical- and cost-effectiveness has been proven in several studies and health technology assessments.
  6. Clotting
    1. Hypercoagulability abnormalities include congenital conditions such as factor V Leiden (activated protein C resistance), prothrombin mutation, protein C and S deficiencies, AT deficiency, antiphospholipid antibodies (LAs), and hyperhomocysteinemia. Evaluation includes thorough history and labs, supported by genetic testing for the patient and family members. However, in the setting of acute illness and elevation of acute-phase reactants, these tests may not be specific. Expert hematologic consultation is recommended in patients who are critically ill.
      1. Medications such as oral contraceptives and smoking or obesity and diabetes should be taken into consideration when patients who are critically ill with hypercoagulability are evaluated. Pregnancy, trauma, and surgery predispose and contribute to the multifactorial process of hypercoagulability.
      2. Treatment is individually tailored. Compression stockings, sequential compression devices, and prophylactic and therapeutic anticoagulation are determined on the basis of history and clinical setting.
    2. Heparin-induced thrombocytopenia is classified as nonimmune mediated (HIT type 1) or immune mediated (HIT type 2).
      1. HIT type 1 is a benign fall in platelet count, usually within 5 days of initiating heparin. The platelet count usually does not fall below 100 000 mm3 and heparin does not have to be discontinued or avoided in the future.
      2. HIT type 2 is immune mediated. IgG antibodies are formed against heparin-platelet factor 4 (PF-4) complexes. This results in platelet activation and aggregation, leading to pathologic platelet aggregation, thrombocytopenia, and vascular thrombosis. HIT antibodies binding to endothelial cell surfaces may result in tissue factor expression and a prothrombotic state.
      3. Up to half of patients undergoing cardiac surgery and 15% of those undergoing orthopedic surgery develop HIT type 2 by immunologic assays (enzyme-linked immunosorbent assay [ELISA]). However, only 1% to 3% of these patients develop clinically significant HIT type 2. This can be significantly reduced using LMWH and eliminated with fondaparinux or DTIs such as argatroban (Figure 27.5). Argatroban is approved for prophylaxis and treatment of thrombosis in patients with or at risk for HIT. In patients with hepatic impairment or multiple organ failure, the argatroban dosage should be decreased to 0.1 to 0.2 µg/kg/min to avoid bleeding complications. Argatroban therapy can be monitored by aPTT. Because aPTT reaches a plateau at higher argatroban plasma concentrations, an overdose may not be recognized. Therefore, ecarin-based assays are more reliable for monitoring DTIs.
      4. Diagnosis is made by history and physical, as well as a decrease in platelet count by 50% from baseline (but usually not <50 000 mm3) within 5 to 14 days of heparin exposure. Previous heparin exposure can lead to a quicker decrease in platelets. Platelet recovery after ceasing exposure to heparin and tachyphylaxis or resistance to heparinization is also suggestive. The clinical 4T score can be used to estimate the probability of HIT type 2 (Table 27.2). For patients with a 4T score of less than 4 points, the probability of having immune HIT is less than 5%. Platelet serotonin release assays (SRAs) are more specific than are ELISA assays, but take longer to obtain. Whole-blood impedance aggregometry can be used as a functional assay for platelet-activating HIT antibodies with a sensitivity and specificity similar to that of SRAs but with a shorter turnaround time. A high index of suspicion in the correct clinical setting (4T score ≥4 points) should be treated as positive for HIT type 2.
      5. Treatment involves discontinuing all exposure to heparin, including heparin-coated catheters, flushes, hemodialysis, or extracorporeal circuitry. Appropriate anticoagulation is essential because 50% to 75% of patients with HIT type 2 develop thrombotic complications. Appropriate anticoagulation is patient specific and would include DTIs such as argatroban. Platelet transfusion should be restrictive because of thrombotic concerns. Longer term anticoagulation (at least 6-8 weeks) will generally be required.
    3. Sickle cell disease is caused by substitution of the amino acid valine for glutamic acid on the β-chain of Hb and is most common in African Americans. Clinical presentation occurs with homozygotes. Similar presentations can occur for homozygotes of sickle cell (SC) or β-thalassemia. Heterozygote carriers usually do not present clinically.
      1. Hypoxia, hypothermia, ischemia, acidosis, and hypovolemia may result in a “sickling” deformity of the RBC. Resultant microvascular obstruction can cause tissue ischemia and infarction. SC crises present with nonspecific signs such as fever, leukocytosis, and tachycardia as well as signs of end-organ dysfunction. Significant anemia can occur because of the shortened lifespan and destruction of the RBCs. Treatment involves addressing the precipitating causes, providing adequate pain relief, and transfusion only when indicated.
  7. Frequent Hematologic Diseases
    1. Hemophilia A is a hereditary disorder of factor VIII and hemophilia B is a hereditary disorder of factor IX. History and physical findings are supported by laboratory findings of an elevated intrinsic pathway clotting time, with a normal PT/INR. Platelet function is normal but the blood clot is unable to be stabilized, so bleeding will recur. Treatment includes factor VIII, factor IX, cryoprecipitate, and desmopressin (DDAVP). rFVIIa and activated PCC (FEIBA [factor eight inhibitor bypassing activity]) are indicated in patients with acquired hemophilia due to inhibitors. Expert hematology consultation is recommended in patients who are critically ill.
    2. Von Willebrand disease is a primarily autosomal-dominant genetic disorder resulting from defects in vWF. vWF normally anchors platelets to collagen while strengthening clotted platelets and stabilizing factor VIII. Treatment includes DDAVP, human factor VIII-vWF complex concentrates, and cryoprecipitate preferably over FFP. In certain patients with acquired von Willebrand disease, high-dose IV gamma globulin has been used successfully. Again, expert hematology consultation is recommended in patients who are critically ill.