Management of coagulation disorders in the surgical intensive care unit

Von Willebrand disease

Von Willebrand disease (vWD) is the most common inherited bleeding disorder, occurring in 1/100 to 1/1000 live births via autosomal inheritance. The disease consists of deficiency or dysfunction of von Willebrand factor (vWF), which promotes platelet adhesion to damaged endothelium and stabilizes factor VIII. There are three types of vWD. Knowing the specific type is important to direct therapy. In type 1, a deficiency of vWF exists. In type 3, vWF is absent. The main subtypes of type 2, 2a and 2b, both consist of a qualitative functional defect in vWF.

Diagnosis of vWD is supported by prolonged partial thromboplastin time (PTT), and in types 1 and 3, reduced levels of vWF antigen. Factor VIII activity may be reduced, and bleeding time or other platelet functional assays may be abnormal. The ristocetin cofactor assay is a test that measures the ability of vWF to induce platelet aggregation.

DDAVP (1-deamino-8- d -arginine vasopressin) may be used to stimulate production of vWF and increase factor VIII levels in type 1 and type 2a disease. It is ineffective in type 3, however, and contraindicated in type 2b because of the risk of thrombocytopenia and increased bleeding. Concentrates of factor VIII vWF are virus inactivated and are used commonly in types 2 and 3, but also in type 1 that is unresponsive to DDAVP. Cryoprecipitate contains vWF and factor VIII and may be used in all types of vWD. However, it is pooled and not virus inactivated. It is only recommended as a third-line therapy. Antifibrinolytic amino acids, such as aminocaproic acid and tranexamic acid (TXA), are used as adjuvant therapy in all types of vWD along with the previously cited treatments.

Hemophilia A

Hemophilia A is a congenital bleeding disorder that results from factor VIII deficiency. It is phenotypically expressed in males because of its X-linked inheritance pattern, whereas females maintain a carrier state. Bleeding tendency is inversely related to factor VIII levels. As with most factor deficiencies, clinical coagulopathy is usually not evident until factor levels fall below 30% of normal (mild hemophilia). Spontaneous bleeding may occur at levels less than 5% (moderate hemophilia), and those with levels less than 1% (severe hemophilia) are especially at risk. Coagulation studies will show a prolonged PTT, normal prothrombin time (PT), and low factor VIII levels.

Patients with clinically significant bleeding or those undergoing surgery should receive factor VIII concentrates, preferably recombinant products. DDAVP increases endogenous factor VIII levels and may be used in mild cases. Up to 20% of individuals may develop IgG antibodies (“inhibitors”) to factor VIII after factor infusion, rendering future treatments ineffective. In such cases, recombinant activated factor VIIa (rFVIIa) may be used to induce hemostasis. This is discussed in more detail later in this chapter. Cryoprecipitate contains factor VIII in lower concentrations than in factor VIII concentrates, but its use is tempered by risks of viral transmission. Viral transmission from pooled factor concentrates is now extremely rare and virtually eliminated with use of recombinant factors.

Hemophilia B

Hemophilia B (Christmas disease) is an X-linked disorder of factor IX deficiency. It is clinically similar to hemophilia A, and coagulation tests also show prolonged PTT with normal PT and low factor IX levels. Recombinant factor IX concentrates are available, as well as pooled donated concentrates. Development of inhibitors is less common (1%) than in hemophilia A, and treatment of severe bleeding may also include rFVIIa. Therapy in such cases should be given in conjunction with a hematologist.

Coagulopathy of trauma

Severely injured trauma patients sustain varying degrees of coagulopathy, caused by a complex interplay of endogenous and exogenous factors, most notably hemorrhagic shock and tissue injury. A specific trauma-induced coagulopathy has been described and is still being elucidated. The tissue damage and hemorrhage due to injury induce a systemic anticoagulation and hyperfibrinolysis due to endothelial injury, activation of thrombomodulin and protein C, inhibition of factor V, and impaired platelet function. Tissue ischemia from shock or direct injury leads to fibrinolysis through release of tPA from endothelium and inhibition of plasminogen activator inhibitor-1. In most cases, some degree of shock is necessary for coagulopathy to be clinically evident shortly after injury; tissue damage or high injury severity alone are not typically associated with clinical coagulopathy. Resuscitation exacerbates the effects of these endogenous stimuli through hemodilution, hypothermia, acidosis, and ongoing tissue ischemia prior to hemostasis. Improvements in resuscitation over the last decade, including use of higher plasma- and platelet-to-red cell ratios, earlier active correction of coagulopathy, use of whole blood, and availability of reversal agents for antithrombotic medications have led to a reduction in the morbidity and mortality from traumatic hemorrhage.

An ongoing debate exists regarding the differences between acute traumatic coagulopathy and disseminated intravascular coagulation (DIC). It has been suggested that traumatic coagulopathy is the same as DIC with the fibrinolytic phenotype (contrasted with the thrombotic phenotype seen in sepsis). Others suggest that these are distinct entities on the same continuum of coagulopathy. Both conditions include a coexisting coagulation and fibrinolysis. DIC may exhibit a more obvious consumptive profile with lower platelets and fibrinogen and depletion of coagulation factors, in contrast to the predominance of inhibition of these raw materials with traumatic coagulopathy. While medical scientists continue to uncover these mechanisms, traumatic coagulopathy in ICU patients should be treated with attention to current evidence-based strategies, especially early hemorrhage control and balanced resuscitation.

Hypothermia

Hypothermia is often seen in the critical care setting in association with the systemic inflammatory response syndrome (SIRS), sepsis, and shock, in which decreased oxygen consumption prevents maintenance of core body temperature. It routinely accompanies major surgery for hemorrhagic shock, in which it exacerbates the coagulopathy and should prompt a “damage control” strategy. In addition, heat loss from hemorrhage is compounded by the administration of room-temperature fluids and blood products. In trauma patients, temperatures less than 32° C have been associated with 100% mortality rate.

Hypothermia slows the rate of reaction of the proteolytic enzymes of coagulation, resulting in impaired hemostasis. Both coagulation enzyme activity and platelet function are impaired at temperatures below 34° C in trauma patients. Platelet dysfunction is multifactorial and is caused by defective adhesion and aggregation and decreased thromboxane production.

Prompt and efficient rewarming is essential in the hypothermic coagulopathic surgical patient. Although controlled hypothermia (targeted temperature management) has proved beneficial in other conditions, such as cardiac arrest, no clear benefit has been proved in trauma or general surgery. The priority of therapy is to treat the underlying cause, whether by stopping any ongoing surgical bleeding, evacuating an undrained abscess, treating infection, or debriding necrotic tissue. External rewarming methods, although slow and inefficient, help to prevent further heat loss. Ambient room temperature should be raised, and warm air blankets and fluid pads applied to the patient (including the head). Core rewarming is far more efficacious than external techniques. At the very least, all infused fluids and blood products should be run through a fluid warmer, and warm humidified air given via the mechanical ventilator. When available, the more aggressive rapid technique of continuous arteriovenous rewarming may be used. A randomized prospective study suggests improved early survival and reduced fluid resuscitation requirements with this method when compared with slower methods.

Acidosis

Metabolic acidosis has long been recognized as a consequence of, and contributor to, coagulopathy. However, the specific pathways whereby acidosis impairs coagulation have yet to be clearly defined. Animal data suggest that hypothermia induces a delayed onset of thrombin formation, whereas acidosis decreases the overall thrombin generation rate. The association of severe acidosis (pH < 7.1) with hypotension and hypothermia in severely injured patients virtually guarantees life-threatening coagulopathy. Therapy is again directed at the cause of acidosis and not merely the correction of the pH. While simultaneously addressing the inciting events, lactic acidosis is treated with fluid resuscitation to optimize tissue perfusion. It can be guided by following the trend in base deficit or lactate level. Sodium bicarbonate administration is ineffective and potentially harmful in lactic acidosis and is not recommended.

Thrombocytopenia

Thrombocytopenia is generally defined as a platelet count lower than 100,000/mm ³ . Counts of 50,000/mm ³ to 100,000/mm ³ increase risk of bleeding with surgery or major trauma, and spontaneous bleeding is a risk below 10,000/mm ³ to 20,000/mm ³ . Thrombocytopenia in the ICU setting has a lengthy differential diagnosis, but its cause can be broadly divided into three categories: decreased production of platelets, consumption or sequestration of platelets, and dilution. Malignancies or chemotherapy may affect platelet production, and massive transfusion and fluid resuscitation can lead to dilution of the total platelet count. In critically ill surgical patients, sepsis can cause a consumptive coagulopathy that in its most severe form manifests as DIC. Platelet consumption also occurs through immune mechanisms (antibodies to platelet glycoproteins), most notably in response to certain drugs. The list of such drugs includes heparin, H ₂ antagonists, sulfa, rifampin, quinidine, hypoglycemics, and gold salts.

Heparin-induced thrombocytopenia is a rare but highly morbid condition associated with a greatly increased risk of thrombosis (see next section). Dilutional thrombocytopenia may occur with massive transfusion because stored blood contains negligible levels of platelets. However, the decrease in platelet count is not proportional to the volume of blood transfusion. Thus, simple dilution is unlikely to be the sole determinant of the low platelet count. Release of platelets from the spleen and bone marrow may partly account for this variability. As with coagulation factors, dilutional thrombocytopenia alone does not account for microvascular bleeding. Treatment and transfusion guidelines are discussed later in this chapter.

Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is an immune-mediated condition, seen with current or recent use of heparin. The risk of HIT is lower with low molecular weight heparin that with the unfractionated form. It causes platelet aggregation and thrombin formation, mediated via IgG antibodies to the platelet factor IV complex. An early form of HIT that is seen in the first 4 days after exposure to heparin does not occur through the immune-mediated pathway and usually does not require cessation of the drug.

Although thrombocytopenia is common in ICU patients and HIT uncommon, the potential of significant morbidity with the latter warrants consideration of the diagnosis in all cases. HIT is characterized by venous and arterial thromboses. The arterial thrombosis from platelet plugs, called “white clots,” are pathognomonic of the disorder. Any focal tissue ischemia consistent with distal arterial occlusion, or unexpected tissue necrosis, should raise suspicion of HIT and be immediately acted upon until HIT can be ruled out.

Diagnosis relies on assessing the probability of HIT and laboratory testing. Detection of HIT antibodies in blood is reported with a measurement of optical density that correlates with the degree of reactivity in the ELISA test. Presence of antibody raises suspicion but is not confirmatory since HIT antibody may be present without hyperthrombosis. While a negative ELISA is reliable to exclude HIT, in positive cases a serotonin release assay (SRA) should be performed. The SRA which detects antibodies specific to HIT and may be combined with an assessment of pretest probability to make the diagnosis. Several scoring systems exist, including 4Ts and the HEP score. The 4Ts score is based on the degree of thrombocytopenia, timing of the drop in platelet count, presence of thrombosis, and other possible causes of thrombocytopenia. The HEP (HIT expert probability) score is based multiple factors including the nadir platelet count and magnitude of the drop; presence of thrombosis, skin necrosis, or bleeding; severe infection, DIC, or indwelling arterial device.

If HIT is suspected, heparin should be stopped and empiric treatment instituted with a direct thrombin inhibitor such as argatroban or lepirudin, or the factor Xa inhibitor fondaparinux. If HIT with thrombosis is confirmed, the American College of Chest Physicians recommends treatment with fondaparinux followed by warfarin.

Disseminated intravascular coagulation

DIC is a syndrome involving diffuse systemic hypercoagulation and fibrinolysis that occurs in response to specific clinical conditions. According to the International Society on Thrombosis and Haemostasis (ISTH) consensus definition, DIC is “a syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes.” Disorders associated with DIC in the surgical ICU include sepsis, trauma, severe pancreatitis, malignancies, fulminant liver failure, and transfusion reactions—among others. The most common cause by far of DIC in the ICU is sepsis. The syndrome involves excessive fibrin deposition in the microvasculature, with platelet aggregation and microvascular thrombosis. The pathophysiology of DIC is linked to the inflammatory cascade and tissue factor (TF) pathway and is reviewed in more detail elsewhere. The condition ranges in severity from a subclinical low-grade acceleration of thrombosis and fibrinolysis to overt pathologic bleeding. Fulminant DIC is associated with multiple-organ dysfunction and death. DIC is often considered a coagulopathy resulting from consumption of clotting factors and platelets, which leaves them unavailable to provide normal coagulation. The result is diffuse bleeding from raw surfaces, catheter insertion sites, the gastrointestinal tract, and other locations. However, DIC may manifest as a thrombotic disorder and is the more common scenario in septic patients. The widespread microvascular thrombosis in such cases leads to organ dysfunction and, in severe cases, organ failure.

DIC may be suspected in the setting of a generalized coagulopathy and clinical microvascular bleeding associated with an underlying process such as those described previously. The laboratory profile includes a low platelet count, prolonged PT and PTT, and elevated fibrin split products (FSPs). D-dimer levels are increased in up to 94% of patients diagnosed with DIC, and the D-dimer assay is the most sensitive test for this condition. Fibrinogen levels may be maintained except in severe forms of DIC.

The International Society on Thrombosis and Haemostasis has provided a scoring system to aid diagnosis of DIC. Points assigned to each parameter appear in parentheses. A total score 5 or higher is compatible with overt DIC, while a score <5 is suggestive of nonovert DIC. Treatment is indicated if signs of bleeding are apparent. In the absence of bleeding, correction of the components of the score is not necessary.

• 1.

  Platelet count (≥100/mm ³ = 0; 50 to <100 = 1, <50 = 2)

• 2.

  Fibrin marker elevation (D-dimer, freeze-dried plasma [FDP]) (none = 0, minimal = 1, moderate = 2, strong = 3)

• 3.

  PT in seconds (<3 = 0; 3 to <6 = 1; ≥6 = 2)

• 4.

  Fibrinogen level g/L (≥1 = 0; <1 = 1)

Therapy for DIC centers on treatment of the underlying disease process to remove the proinflammatory stimulus of the syndrome. Clinical hemostasis is the goal. Platelet counts and the PT/PTT are used to guide response to therapy, but are not endpoints themselves. Fresh frozen plasma (FFP) and platelet transfusion are indicated in patients with active bleeding and those with significant laboratory derangements undergoing surgery or procedures. Cryoprecipitate may be considered to replace fibrinogen if fibrinogen levels fall below 100 mg/dL and are not corrected with FFP infusion.

Many other therapeutic agents have been investigated, but to date no specific treatment has proved successful in improving outcome in patients with DIC. Anticoagulation has been used to attempt to control the hypercoagulation in DIC, and although improvement in certain laboratory parameters has been reported, no survival benefit has been demonstrated with low-molecular-weight heparin (LMWH), thrombin inhibitors, or antifibrinolytics.