Coagulopathies

The term coagulopathy can denote problems with hypercoagulability or bleeding diatheses. This chapter will focus on the latter. See chapters on Disseminated Intravascular Coagulation, Heparin-Induced Thrombocytopenia, Antiphospholipid Antibody Syndrome, and Venous Hypercoagulability for more information on hypercoagulable states.

The coagulation cascade is a complex interaction of coagulation factors, co-factors and enzyme complexes which together lead to secondary hemostasis by generation of a fibrin clot to solidify the initial platelet plug formed by primary hemostasis. Without successful secondary hemostasis, there is clot breakdown and bleeding.

Patients with coagulation factor disorders may present with difficulty to control bleeding, especially after a challenge such as surgery or childbirth. Alternatively, patients may be asymptomatic but have abnormalities detected on laboratories, such as prolonged prothrombin time (PT) or partial thromboplastin time (PTT).

The diagnostic approach and management will vary depending on the clinical context. In a patient with abnormal coagulation tests on incidental laboratory studies, the physician should first question whether the finding has clinical relevance. Conversely, patients with acute bleeding will need immediate intravascular resuscitation while pursuing a rapid diagnosis.

Disorders of coagulation may be either congenital or acquired. In the bleeding patient, consider abnormalities of platelets and the vascular endothelium in addition to coagulation factor disorders.

Low levels of multiple coagulation factors, single coagulation factor deficiencies, consumptive processes that deplete coagulation factors, and inhibitors of coagulation factors can all lead to inadequate fibrin clot formation and therefore bleeding.

It is helpful to group coagulopathies broadly into processes that prolong the PT, prolong the PTT or prolong both.

Recall that the PT is used to assess the extrinsic pathway of the coagulation cascade and is influenced by levels of factor VII. The PTT assesses the intrinsic pathway and is affected by factors VIII, IX, XI, and XII. Factors II (prothrombin), V and X are common to both the extrinsic and intrinsic pathways, and processes affecting these factors will generally lead to disturbances of both the PT and the PTT.

The liver is the major site of synthesis of coagulation factors, with the exception of factor VIII which is also produced by endothelial cells and cells of the reticuloendothelial system. Factors II (prothrombin), VII, IX, and X are vitamin K-dependent.

Bleeding related to defects in secondary hemostasis (coagulation factor abnormalities) can be distinguished from defects in primary hemostasis (platelet abnormalities) by the timing and type of bleeding. For example, problems with platelets often involve mucocutaneous sites whereas issues with coagulation factors usually involve deep tissue and synovial diatheses.

Given the variability in patient perceptions and descriptions of bleeding, use of a standardized bleeding assessment tool may aid in the evaluation of patients with disorders of hemostasis.

In a patient with suspected coagulopathy, inquire about previous hemostatic challenges such as surgery, childbirth, dental procedures, or trauma. To help determine severity of past bleeding, ask specifically about episodes that required hospitalization, transfusions or re-operation.

A history of bleeding since early childhood suggests a hereditary bleeding disorder. While a positive family history of bleeding problems also suggests an inherited coagulopathy, the absence of a family history of bleeding does not exclude the possibility of a hereditary bleeding disorder.

In patients with suspected coagulopathy, it is of central importance to inquire about all medications, including prescribed, over-the-counter and herbal. This includes aspirin, NSAIDs, clopidogrel, ticagrelor, prasugrel, ticlopidine, and other medications that exert anti-platelet effects. Warfarin and heparin products cause iatrogenic defects in secondary hemostasis.

Vitamin K is required for coagulation factor metabolism. Therefore, deficiency in this vitamin due to dietary or malabsorptive processes may contribute to coagulopathy. Examples include: cystic fibrosis, primary biliary cholangitis, primary sclerosing cholangitis, biliary atresia, celiac disease, inflammatory bowel disease, and short bowel syndrome. The vitamin K-dependent coagulation factors are synthesized in the liver. Therefore, advanced liver disease may also cause bleeding.

Warfarin blocks liver uptake of vitamin K, inhibiting the vitamin K-dependent carboxylase responsible for post-transcription modification of factors II (prothrombin), VII, IX, and X. While factor II (prothrombin) and factor X affect both the PT and the PTT, factor VII affects only the PT and has the shortest half-life. Prolongation of the PT is typically reported as the international normalized ratio (INR) and is the most accurate measurement of the therapeutic effect of warfarin.

Heparin potentiates the action of anti-thrombin III, leading to increased inactivation of thrombin and factor Xa. The PTT is highly sensitive to unfractionated heparin and is used to monitor for therapeutic heparin levels.

Coagulopathies are usually suspected on the basis of clinical features of bleeding, as described above, which then prompt measurement of the PT and PTT.

In the setting of prolonged PT or PTT, the patient’s plasma is combined with normal plasma and the test repeated (called a mixing study) to differentiate between the presence of factor inhibitors (PT or PTT do not correct) or factor deficiency (PT or PTT correct). If mixing studies do correct the prolonged PT or PTT, then individual factor activity levels can be measured to identify the deficiency.

In patients with suspected coagulopathy, the first step in evaluation is measurement of the PT and PTT.

When investigating the cause of a prolonged PT or PTT (especially in a patient without evidence of bleeding) consider artifact. Too little blood in the sample or heparin contamination can lead to prolonged PT or PTT. Blood samples that are hemolyzed, icteric, lipemic, or collected from patients with polycythemia may have artificially prolonged PTT.

Once artifact is excluded, assess for use of anticoagulants, such as Coumadin, heparin or direct thrombin inhibitors. Mixing studies differentiate between factor deficiencies (which correct with mixing studies) and inhibitors (which do not correct with mixing studies).

When factor deficiencies are suspected, the etiology can usually be determined by checking a limited number of factors, keeping the following facts in mind:

• Factors II (prothrombin), VII, IX, and X are vitamin K-dependent.

• Factor VII is the only factor that affects the PT without affecting the PTT.

• The liver is the major site of synthesis of coagulation factors, with the exception of factor VIII which is also produced by endothelial cells and cells of the reticuloendothelial system.

For example, in a patient with prolonged PT that corrects with a mixing study who has evidence of liver disease but also risk factors for vitamin K-deficiency, checking factor V and VII will distinguish between the two possible etiologies. Deficiencies in either factor V or factor VII can lead to prolonged PT, but factor V is not vitamin-K dependent and therefore should be normal in vitamin K-deficiency. Alternatively, a trial of vitamin K replacement can distinguish between these two entities.

Similarly, in a patient with a prolonged PT and PTT, factor VIII can be helpful in distinguishing between disseminated intravascular coagulation (DIC) and severe liver disease. In DIC, all factors are consumed, so factor VIII will be low. However, even in the setting of severe liver disease, factor VIII levels should be normal as factor VIII is also produced in the endothelium.

Although guidelines recommend against routine coagulation testing pre-operatively, patients planned for invasive procedures are often “screened” for bleeding risk with platelet count and PT/PTT testing.. However, this laboratory “screening” should never take the place of obtaining a bleeding history from the patient. A thorough bleeding history is recommended for all patients, even those with normal “screening” tests, as there are bleeding disorders in which the PT and PTT are normal, but life threatening delayed bleeding after trauma occurs (factor XIII deficiency). Evidence suggests that bleeding history is similarly poor in predicting perioperative bleeding. Preoperative measurements of hematocrit and platelet levels are recommended by the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists.

As discussed above, the approach to the patient will depend on the clinical context. Patients who are acutely bleeding with suspected coagulopathy need large bore intravenous (IV) access, aggressive resuscitation and blood transfusion while planning the approach to bleeding control, which may involve surgery, interventional radiology or endoscopy.

When results of basic coagulation studies support the presence of a coagulopathy (or in the setting of massive transfusion), the following products can be considered:

• Fresh frozen plasma (FFP): Start with a dose of 10-15 mL/kg, which is typically 3-5 units for an average adult. Recall that each unit is 250 mL, so volume overload can become an issue when multiple units are necessary. FFP contains all factors present in plasma, and should not be used when specific factor deficiencies are known (i.e. if known factor VIII deficiency, use concentrated factor VIII) unless required emergently. Complications include infection, hemolytic transfusion reaction, transfusion-related acute lung injury (TRALI), and volume overload.

• Cryoprecipitate: Cryoprecipitate is rich in fibrinogen, factor VIII and von Willebrand factor. One unit of cryoprecipitate contains the amount of fibrinogen present in one whole unit of blood (approximately 200 to 400 mg) and will typically raise the plasma fibrinogen by 7 to 10mg/dL (goal fibrinogen level for normal hemostasis is 75 to 100 mg/dL). Each unit of cryoprecipitate is approximately 15 mL.

• Vitamin K: Use in suspected nutritional vitamin K deficiency or in the setting of warfarin use that needs to be reversed. In stable patients without acute bleeding, oral administration is not recommended below an INR level of 10. In patients taking vitamin K antagonists with INRs >10, oral vitamin K is preferred due to the potential risks of hypersensitivity and anaphylactoid reactions. In acute major bleeding with any INR elevation, the 2012 ACCP guidelines recommend administration of four-factor prothrombin complex concentrate (PCC) and IV vitamin K 5-10 mg (Guyatt, 2012). The only available four-factor PCC in the U.S. is Kcentra. Therefore, FFP is typically given. Ten milligrams IV should improve the INR in 4-6 hours.

The presence of prolonged PT and PTT with thrombocytopenia should raise the suspicion of DIC, which needs to be rapidly recognized and the underlying cause (i.e. sepsis, malignancy) identified and treated. Supportive care with platelets, cryoprecipitate (for fibrinogen) and fresh frozen plasma (for coagulation factors) is often necessary.

Because of the volume associated with multiple units of FFP, volume overload is a known side effect of treatment with FFP. This can be managed with concurrent diuretic administration in the patient with adequate renal function.

Although no prospective randomized trials have definitively addressed the efficacy of FFP transfusion for mild to moderate prolongation of PT, retrospective studies of FFP transfusion in this situation have not shown benefit in terms of normalization of INR or decreased estimated blood loss. For example, in one retrospective study of patients with INR between 1.1 and 1.85, FFP transfusion normalized the INR in only 0.8% of patients.

Considering the unclear benefits and known adverse reactions associated with FFP transfusion (TRALI, volume overload), plasma therapy should be carefully scrutinized in patients with minimally elevated INR.