Critical Care Medicine

Coagulopathies and bleeding disorders; Hemorrhage, Clotting Abnormalities, Microvascular Bleeding

Bleeding and Coagulopathies

Synonyms

Hemorrhage, Clotting Abnormalities, Microvascular Bleeding

Related Conditions

Acquired Coagulopathies (thrombocytopenia, disseminated intravascular coagulation, coagulopathy of liver disease, drug-induced platelet dysfunction, hyperfibrinolysis, acquired clotting factor inhibitors)

Inherited Bleeding Disorders (Hemophilia A, Hemophilia B, Other Clotting Factor Deficiencies, Qualitative Platelet Disorders, Inherited Thrombocytopenia, Vascular Abnormalities)

Abnormal coagulation tests without bleeding

1. Description of the problem

Bleeding symptoms will be affected by the underlying medical issues in the patient. Patients with systemic infections may be thrombocytopenic with or without the presence of DIC. Patients with liver disease can have different bleeding symptoms depending on the manifestation of their liver disease. Portal hypertension can present with variceal bleeding without other evidence of a coagulopathy. If there is sufficient impairment of coagulation factor synthesis, mucocutaneous bleeding can be present. Drug-induced thrombocytopenia is common in hospitalized patients.

Hemostasis Testing Abnormalities without Clinical Bleeding: In a patient who is not bleeding but who has coagulation testing abnormalities, further evaluation to determine the cause of the coagulation test abnormality should be performed prior to any treatment. Pseudothrombocytopenia, incorrect filling of the Na citrate-anticoagulated (blue top) tube, and heparin contamination secondary to line flushing are common findings.

In assessing the bleeding critically ill patient, it is useful to obtain historical data if available on whether the patient or the patient's family has a history of significant bleeding, spontaneously or in response to trauma or procedures. In patients with a personal or family history of bleeding, any diagnostic information that is available from outside physicians should be obtained. A family history of bleeding helps in narrowing the diagnosis. The type and location of past bleeding is informative. Patients with inherited coagulation factor deficiencies can have hemarthroses, while mucous membrane bleeding, particularly epistaxis and menorrhagia, is a hallmark of platelet disorders and von Willebrand disease.

Hemostasis Testing Abnormalities without Clinical Bleeding: Abnormalities may be present on screening laboratory testing that suggest a bleeding disorder in individuals. Coagulation laboratory testing should be interpreted in the setting of the patient's clinical presentation. Thrombocytopenia as well a prolonged activated partial thromboplastin time (aPTT) and/or prothrombin time (PT) may not indicate an underlying bleeding disorder.

2. Emergency Management

In patients who are bleeding and unstable due to the bleeding, the first priority is to identify the most likely cause for the bleeding and select treatment based upon the cause for the bleeding.

In the absence of an identified cause for severe bleeding, which is apparently associated with a defect in coagulation, the use of recombinant factor VIIa is not uncommon. The data to support its use in uncontrolled hemorrhage are somewhat limited, but the large number of anecdotal reports of its hemostatic advantage over conventional therapy has been noteworthy. The off-label use of recombinant factor VIIa for intractable bleeding has increased bit because of its cost, there is now a significant concern that the large number of anecdotal reports are not accompanied by clinical trials which support its use for intractable bleeding. The major concern regarding its use for intractable bleeding is the risk of thrombosis following its infusion, particularly in the first 3-4 days after receiving the drug. It has not been determined whether the observed thrombotic events in patients treated with recombinant factor VIIa are due to pre-existing conditions that predispose to thrombosis, such as a heritable hypercoagulable state like a factor V Leiden mutation.

3. Diagnosis

Thrombocytopenia is a commonly encountered condition in the ICU. The first consideration of possible causes for thrombocytopenia in the bleeding patient is decreased platelet production versus increased platelet destruction. Leading causes of decreased platelet production include invasion of the bone marrow by tumor cells or by scarring and treatment with cytotoxic chemotherapy. Leading causes of increased platelet destruction in the ICU patient are DIC and heparin-induced thrombocytopenia (HIT). It is important to understand that HIT is a thrombotic disorder and not a bleeding disorder, despite the low platelet count. Many other drugs can induce thrombocytopenia, though it is not possible to predict which patients will decrease the platelet count upon exposure to the drug. Another common cause of increased platelet destruction is ITP, but this is less frequently encountered in the ICU. A falsely low platelet count resulting from EDTA activation of platelets in the tube used to collect the blood should be considered, particularly when there is spuriously low platelet count after many normal platelet counts.

Platelet function is impaired in many ICU patients. The most common cause of impaired platelet function is exposure to antiplatelet agents, notably aspirin, Plavix, Prasugrel, Ticagrelor, glycoprotein IIb/IIIa inhibitors, and nonsteroidal anti-inflammatory drugs such as ibuprofen, among other compounds. The bleeding time test is not a useful indicator of platelet function. In addition, standard platelet aggregation studies with platelet-rich plasma are too cumbersome to perform and are impractical for routine assessment of platelet function. Platelet function tests that are simple to perform but still have some practical challenges for routine testing include the VerifyNow test and the platelet function analyzer (PFA-100). It is important to note that the results of these tests do not always agree, leading to uncertainty about the status of platelet function. In the absence of tests for platelet function, if a bleeding patient in the ICU has a normal platelet count and a normal PT and PTT, and the bleeding is coagulopathic, a defect in platelet function should be strongly considered as a cause for the bleeding.

A common inherited bleeding disorder that affects both men and women is von Willebrand disease. Up to 1% of the population has a level of von Willebrand factor that could result in excess bleeding with a challenge to hemostasis. The platelet count, the PT, and the PTT are usually normal in the von Willebrand patient, requiring the performance of the tests for von Willebrand factor or its functional correlate, called the ristocetin cofactor assay. A bleeding patient in the ICU with a history of bleeding over time or excess bleeding with surgery and normal routine coagulation laboratory tests should be considered for von Willebrand disease.

Bleeding patients in the ICU often have a prolonged PT, a prolonged PTT, or both. These prolongations must be further evaluated with additional tests to determine the underlying cause of the abnormality. The treatment is based upon the actual cause of the prolongation of the PT and/or PTT. A common mistake is to not investigate the cause of a prolonged PT or PTT and simply transfuse the patient with fresh frozen plasma. In some cases, plasma is not likely to stop the bleeding and in others more effective therapy is bypassed because the underlying cause remains unidentified. The further evaluation of a prolonged PT or PTT with relevant coagulation factor assays nearly always leads to the identification of a specific disorder. Common causes that prolong the PT and/or PTT in ICU patients and are associated with bleeding include DIC, vitamin K deficiency, liver disease, anticoagulant overdose, and a selective coagulation factor deficiency.

4. Specific Treatment

Platelet transfusions are typically effective for patients with decreased platelet production because the transfused platelets are not destroyed. Transfusion with platelet concentrates may be useful to control bleeding in the DIC patient to replace the platelets that are lost in the formation of clots in the microcirculation. In patients with very active DIC, transfusion of platelets may result in hemostasis while only mildly increasing platelet count.

Importantly, platelet transfusions are highly contraindicated in HIT patients, as this can promote the development of large thrombi that result in amputation, stroke, and venous thrombosis, all of which can produce death. Platelet transfusions are unlikely to increase the platelet count in the ITP patient because the infused platelets become coated with antiplatelet antibodies that lead to platelet destruction in the spleen.

If patients exposed to antiplatelet agents are transfused with platelet concentrates, the transfused platelets may or may not function normally, depending upon the drug that is present in the circulation. In the aspirin-treated patient, because aspirin inhibits the platelets in circulation but then quickly disappears from the blood, with a half-life of less than 15 minutes, transfused platelets into an aspirin-treated patient can be functional.

This is different from Plavix, Prasugrel and Ticagrelor, which have antiplatelet effects on transfused platelets for several days after ingestion of the drug. At this time, a recommendation has emerged called the "3, 5, 7 rule." The time for discontinuation prior to surgery is 3-4 days for Ticagrelor (it is reversible), 5 days for Plavix, and 7 days for Prasugrel, if waiting is possible.

Glycoprotein IIb/IIIa inhibitors are powerful platelet antagonists that can result in bleeding following treatment with these drugs. They can also in rare cases produce a profound thrombocytopenia.

Treatment options for the ICU patient with von Willebrand disease include semi-purified preparations of factor VIII that also contain von Willebrand factor (Humate P is one example), intravenous DDAVP if there are no issues related to volume overload, and cryoprecipitate.

Treatment with fresh frozen plasma to reduce a prolonged PT and/or PTT toward normal may be useful to stop the bleeding in the DIC patient. Several rounds of transfusions with platelet concentrates and fresh frozen plasma may be required to stop the bleeding. In cases of severe DIC, however, with extreme consumption of platelets and coagulation factors, treatment with fresh frozen plasma and platelets may still be inadequate to stop the bleeding.

Patients with vitamin K deficiency, which for an ICU patient may be a result of chronic antibiotic therapy, can be treated with vitamin K. Vitamin K can be administered orally, subcutaneously, and intravenously, but it carries a risk for anaphylaxis when delivered intravenously. When possible, the use of oral vitamin K at doses from 1 mg to 2.5 mg should be used with the expectation of a substantial reduction of INR within 8 to 24 hours. Although subcutaneous injection of vitamin K has been widely used, this route of administration does not reduce supratherapeutic INR values faster than 1 mg of oral vitamin K. A 1 mg dose of oral vitamin K reduces the INR more rapidly and more reliably than subcutaneously delivered vitamin K. Therefore, subcutaneous injection of vitamin K is not recommended. A significant reduction in the INR can be expected within 4 to 6 hours after intravenously delivered vitamin K. Typically, 5-10 mg is added to 50 mL of D5W and infused over 15 to 30 minutes.

Infusion of K-Centra, a complex of 4 of the vitamin K dependent factors (II, VII, IX, X), can be used to immediately restore the vitamin K-dependent factors to stop the bleeding in a patient with severe vitamin K deficiency.

Subcutaneously administered vitamin K to a patient with normal liver function should significantly reduce the PT and/or PTT toward normal over 12 to 24 hours. Patients with severe liver disease may have a severe coagulopathy associated with both thrombocytopenia and decreased coagulation factors. In the patient with liver disease who also has a large spleen, the use of platelet concentrates to halt a bleeding episode may be effective even if the platelet count does not significantly rise. Fresh frozen plasma is likely to decrease a prolonged PT and/or PTT value toward normal. However, patients with liver disease often fail to completely normalize the PT and PTT even when transfused with large volumes of plasma.

If the PT and the PTT are within several seconds of the upper limit of the normal range, and the bleeding has stopped, discontinuation of fresh frozen plasma transfusion avoids the risk of fluid overload. In some patients with severe liver disease, or in patients with DIC, the plasma fibrinogen concentration may decrease below 100 mg/dL. In these patients, transfusion with cryoprecipitate, which is rich in fibrinogen, may be useful to control a bleeding event.

Cryoprecipitate does not contain all of the coagulation factors, so it is often necessary to transfuse fresh frozen plasma along with cryoprecipitate. Fresh frozen plasma also contains fibrinogen, although it is not enriched with this factor, and therefore transfusion with fresh frozen plasma could correct the fibrinogen deficiency without the need for additional transfusion with cryoprecipitate.

For bleeding patients in the ICU who are being treated with anticoagulants, a reversal of the anticoagulant effect should be considered as a first line of treatment . For unfractionated heparin, protamine can be used to reverse the heparin effect.

For low-molecular-weight heparin, such as Lovenox and Fragmin, protamine reverses a significant portion of the anticoagulant effect and may be effective in treating a bleeding episode from overdose of these anticoagulants.

There is no antidote for fondaparinux, which has a long half-life of approximately 20 hours and cannot be used in patients with impaired renal function. Use of this drug to prevent thrombosis is particularly problematic for use in the ICU for those reasons.

There is also no antidote for argatroban and dabigatran, which are direct thrombin inhibitors. The half life of argatroban is less than one hour, and therefore the anticoagulant effect of these compounds dissipates quickly and permits a bleeding episode associated with overanticoagulation to stop spontaneously within a short time in many cases.

For the bleeding ICU patient who has recently been treated with warfarin, warfarin should be discontinued. Treatment with K-Centra and vitamin K is a first line of therapy for life-threatening bleeding. If the bleeding is not life-threatening, the use of Vitamin K without K-Central is preferred.

Some opinion leaders suggest the use of certain prothrombin complex concentrate rather than fresh frozen plasma to control life-threatening bleeding in the warfarin overdose patient. If the bleeding is not life-threatening, the use of vitamin K without fresh frozen plasma is preferred.

Not all selective coagulation factor deficiencies are rare. Of those that are not rare, factor VIII deficiency (hemophilia A) and factor IX deficiency (hemophilia B) can be treated with recombinant factor VIII or factor IX to control a bleeding episode. Bleeding patients with factor VII deficiency can be treated with fresh frozen plasma or recombinant factor VIIa to restore adequate amounts of factor VII. Factor XI deficiency, which is common in patients of Jewish descent, is not always associated with a predisposition to bleeding, even when the level of factor XI is extremely low.

In the factor XI-deficient patient with a personal or family history of bleeding, treatment with fresh frozen plasma can be used to control a bleeding episode. Fresh frozen plasma should be avoided to simply elevate the factor XI level in a patient who has had multiple challenges to hemostasis without excess bleeding.

Similarly, fresh frozen plasma should be avoided to elevate the factor XII level and shorten the PTT, because for this factor, even severe deficiencies are not associated with an increased risk for bleeding. A lupus anticoagulant can also elevate the PTT, and fresh frozen plasma should not be administered to such patients to attempt to shorten the PTT because the lupus anticoagulant does not represent a bleeding disorder in vivo.

For patients who are bleeding as a result of hyperfibrinolysis, treatment with epsilon aminocaproic acid (Amicar) or tranexamic acid may be useful to control bleeding. It is important, however, to rule out the presence of DIC prior to the use of these compounds because in DIC patients, treatment with these compounds can promote the generation of thrombosis.

5. Disease monitoring, follow-up and disposition

Follow-up

Thrombocytopenias with a variety of etiologies: follow platelet count.

Factor deficiencies as a result of a variety of causes: follow PT and PTT

Platelet function disorders: follow with platelet function test like VerifyNow or PFA-100.

Wrong diagnosis

Suspect a wrong diagnosis when standard therapy fails to improve patient outcome.

Pathophysiology

When an injury to the blood vessel wall disrupts its integrity, bleeding can result. To stop the bleeding, the blood vessel wall contracts, which promotes the interaction of circulating platelets with the cut surface and the subsequent adherence of the platelets to von Willebrand factor in the cut surface.

The initially adherent platelets release substances into the blood, notably thromboxane and ADP, and this results in the formation of a large platelets aggregate that serves as a plug to stop the bleeding. The platelet plug is then stabilized by the final product of the coagulation cascade, fibrin. The repair of the blood vessel wall involves degradation of the platelet plug and fibrin in the process of fibrinolysis.

With these processes in mind, bleeding can occur when: 1) the injury to the blood vessel wall is too large to permit platelet aggregation and platelet plug formation to stop the bleeding; 2) there are not enough platelets; 3) there are enough platelets but platelet function is impaired; 4) fibrin formation is slow or insufficient; and 5) fibrinolysis occurs too rapidly or too extensively.

Epidemiology

Most bleeding is a result of a structural lesion. If the ICU patient is bleeding from a single site, the likelihood of bleeding from a structural lesion, rather than a coagulopathy, is high. On the other hand, if bleeding is occurring from multiple sites, it is more likely that the patient is suffering from a coagulopathy. For example, the evaluation of the patient who is bleeding from the gastrointestinal tract with diagnostic studies to locate a structural lesion is obviously very different from the evaluation of a patient for coagulopathy.

Prognosis

Poor prognosis is associated with persistent severe thrombocytopenia (less than 10,000/uL) that is refractory to platelet transfusions; prolonged PT or PTT values that show modest reductions toward normal with plasma or factor concentrates; impaired platelet function, often because of administration of antiplatelet medications that permanently inactivate platelets.

Special considerations for nursing and allied health professionals.

N/A

What's the evidence?

Dres, RE. "Critical issues in hematology: Anemia, thrombocytopenia, coagulopathy, and blood product transfusions in critically ill patients". Clin Chest Med. vol. 24. 2003. pp. 607.

Wheeler, AP, Rice, TW. "Coagulopathy in critically ill patients: Part 2 -- Soluble clotting factors and hemostatic testing". Chest. vol. 137. 2010. pp. 185.

Kor, DJ, Gajic, O. "Blood product transfusion in the critical care setting". Curr Opin Crit Care. vol. 16. 2010. pp. 309.

Levi, M, Opal, SM. "Coagulation abnormalities in critically ill patients". Crit Care. vol. 10. 2006. pp. 222.

Spahn, DR. "Management of bleeding following major trauma: A European guideline". Crit Care. vol. 11. 2007. pp. 414.

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