Chapter 46: Bleeding Disorders and Coagulopathy Reversal

The issue of LMWH use is commonly seen with patients and presents clinicians with a significant dilemma. It is common practice to stop all anticoagulation and antiplatelet agents once intracerebral hemorrhage (ICH) is detected. However, the diagnosis can sometimes be delayed, and the situation would be quite different if she had continued her LMWH. Reversal of anticoagulation, in the setting of continued, active bleeding, must be done on an emergent basis. The half-life of LMWH is 12 to 24 hours. There is no antidote that completely reverses the effect of LMWH, and such reversal reports are mostly anecdotal in the literature. Protamine sulfate is used intravenously to reverse unfractionated heparin and leads to full reversal. It is thought that protamine reverses approximately 60% of the effect of LMWH^{1, 2} based on in vitro studies.

It is unclear why protamine does not fully neutralize the anti-Xa activity of LMWH. One milligram of protamine is given for every 100 units of active unfractionated heparin, and per 1 mg of LMWH.³ The maximum dose of protamine is 50 mg, with a maximum infusion rate of 5 mg/min. Hypotension, severe anaphylaxis, and death have been reported with protamine use.⁴ These adverse reactions can often be minimized by premedication with antihistamines and steroids, as well as a slow rate of administration. If given in excess dose, protamine can have a paradoxical anticoagulant effect.

There are small studies describing recombinant activated factor VII (rFVIIa) for LMWH reversal, with some success. Doses in these studies ranged from 20 to 90 μg/kg.^{5, 6} The use of rFVIIa in the setting of spontaneous and warfarin-associated bleeding will be discussed later in this chapter.

A safe time to reinitiate full anticoagulation is determined on a case-by-case basis. If hematoma expansion does not occur and the patient doesn't receive decompressive surgery, in general, full anticoagulation may be resumed approximately 10 to 14 days after the bleeding episode. The decision as to when reinitiation of anticoagulation can occur in this setting must be decided with risk-benefit stratification.

The goal in this case would be rapid reversal of the underlying coagulopathy. For deep brain hemorrhages, neurosurgical intervention is usually not advocated. Warfarin functions as an anticoagulant by inhibiting the biosynthesis of vitamin K–dependent procoagulant factors II, VII, IX, and X.⁷ Higher risk of intracranial hemorrhage is associated with the intensity of anticoagulation.⁸ But often, as in this case, patients on warfarin present with ICH with an INR within therapeutic range.⁹ In oral anticoagulant–associated ICH, the risk of continued bleeding is very high. In patients with ICH, the use of warfarin increases the risk of progressive bleeding and decompensation and doubles the risk of death.^{10, 11} It is imperative that reversal of coagulopathy is initiated immediately. Treatment consists of vitamin K, fresh-frozen plasma (FFP), and prothrombin-complex concentrates (PCCs).

Vitamin K

The patient should immediately receive vitamin K 10 mg intravenously (IV) over 10 minutes to begin the reversal of warfarin, which can take 6 to 24 hours. Vitamin K administration is necessary for the sustained reversal of the INR. American College of Chest Physicians guidelines recommend IV vitamin K in the face of life-threatening bleeding disorders.¹² While anaphylaxis reactions have been reported with intravenous administration of vitamin K, the overall incidence is rare, 3 per 10,000 doses.^{13, 14} Anaphylaxis reactions have also been reported with nonintravenous routes of administration.¹⁵ In addition, the absorption of subcutaneous vitamin K can be unpredictable.¹⁶ Therefore, intravenous vitamin K is the preferred route of administration in this setting.

Fresh-Frozen Plasma

FFP may be used at a dose of 15 mL/kg to achieve prompt reversal of warfarin by providing factors II, VII, IX, and X. These are the factors that are vitamin K dependent and those that warfarin suppresses. However, obtaining FFP can take quite some time. After the request arrives at the blood bank, the FFP must be blood-type matched and thawed, which can lead to an unacceptable delay in the face of a life-threatening hemorrhage. Volume status is also a concern, as the amount of FFP needed to fully and continuously reverse the coagulopathy may not be possible without infusing an unacceptably high volume intravenously. The usual goal is to achieve an INR of less than 1.5, which reflects functioning of at least 40% of coagulation proteins, which is considered adequate for hemostasis.¹⁷ A typical unit of FFP contains 200 to 250 mL, and 1 unit typically lowers the INR by approximately 10%. One unit of plasma will raise coagulation factors by 2.5%. Patients usually require 6 to 12 units of FFP and frequently even more, which leads to increased risk of volume overload and pulmonary edema. Severe allergic reactions, transfusion-associated circulatory overload, and transfusion-related acute lung injury (TRALI) can occur with FFP transfusion.¹⁸

Prothrombin-Complex Concentrate

PCCs are derived from large donor plasma pools and contain factors II, VII, IX, and X. They are highly concentrated coagulation factor replacement compounds. They were originally developed for the treatment of hemophilia patients with inhibitors. They are rapid, in small volume, with no need for typing and cross-matching. They have been found to normalize the INR more rapidly than vitamin K or FFP alone.^{19, 20} Large randomized trials comparing FFP to PCCs are currently ongoing.

While these products are licensed for warfarin reversal in Europe, none are licensed for this indication in the United States. Two PCCs are commercially available in the United States, and these products contain variable amounts of factor VII (Table 46-1). Clinicians need to be cautious when using PCCs in patients in whom there is a suspicion of disseminated intravascular coagulation (DIC) as thromboembolic events have been reported. While PCCs are generally considered safe to use, one should avoid the use in patients with DIC, hyperfibrinolysis, and a history of thromboembolism.

Recombinant Activated Factor VII

Factor VIIa is indicated for the treatment of hemophilia patients with inhibitors as well as patients with factor VII deficiency. Many studies have been published regarding the use of rFVIIa in the setting of spontaneous and warfarin-associated bleeding. Variable doses (10-90 μg/kg) have been used in studies attempting to reverse warfarin anticoagulation in the setting of ICH. These studies consist of case reports, case series, and retrospective cohort studies. Factor VIIa was found to lead to rapid reversal of the INR in these studies.^{21, 22, 23, 24, 25} Due to the varied dosing, end points assessed make it difficult to draw any other conclusion. However, in the phase III Factor VII for Acute Hemorrhagic Stroke Treatment (FAST) trial, which assessed the use of rFVIIa in spontaneous, noncoagulopathic hemorrhage, there was a reduced hematoma expansion rate with the drug despite no improvement in long-term clinical outcomes (refer to Chapter 2, Intracranial Hemorrhage, for more detail). It is important to note that rFVIIa corrects the prothrombin time or INR, but this does not always correlate with cessation of bleeding.²⁶

Thromboembolic complications have occurred in this setting and rVIIa use. In the FAST trial, a 5% absolute increase in the number of arterial thrombotic events was found in the group treated with the highest dose (80 μg/kg) of rFVIIa. Thus, particular caution should be used in patients with underlying thrombotic risk.

This is an ideal scenario for considering the use of IV vitamin K 10 mg and PCC 50 units/kg (Table 46-2). PCC has been associated with thrombosis in recipients with hemophilia,²⁷ but in a review of PCC-treated patients, very few thrombotic episodes have been recorded.²⁸ In a 2008 publication,²⁹ Leissinger and colleagues reviewed the published evidence on the role of PCC in warfarin reversal. They identified 14 studies that included 460 patients, and 7 thrombotic complications were reported. There were no episodes of DIC. Overall, the thrombotic risk associated with the use of PCCs is reported to be low although not negligible.

Oral manipulation bleeding is a major clinical manifestation of a bleeding disorder as saliva contains a high concentration of fibrinolytic proteins. An appropriate workup includes mixing studies to rule out an inhibitor, a lupus anticoagulant, and an artifact, and if corrected factor deficiencies need to be ruled out. Factors VIII, IX, and XI are the most common.

Ensuring hemostasis after surgery would be the goal. An algorithm for the management of the different deficiencies, including von Willebrand, is shown in Table 46-3.

Preoperatively, one's goal is to reach 100% correction and never let the factor fall below 30% to maintain adequate hemostasis. It is important that aminosalicylic acid (ASA), nonsteroidal anti-inflammatory drugs (NSAIDs), and other antiplatelet agents not be used when levels are low, but they are acceptable during replacement therapy. Factor XI–deficient patients do not have available a concentrate in the United States, but do in many other countries. Therefore, we treat with FFP and do not need to achieve similar levels to achieve hemostasis.

The occurrence of DVT in postneurosurgic intervention is a well-known complication. Thrombosis in the setting of glioblastoma multiforme is particularly common, with an incidence rate of 20% to 24%.^{30, 31, 32, 33} As this case was a recurrence of a tumor that had been surgically resected 8 months prior and the patient had previously been exposed to heparin, one must be vigilant about the risk of development of heparin-induced thrombocytopenia (HIT) with thrombosis (Figure 46-1). As neoplastic disorders are frequently associated with DIC, one must rule out DIC as well (see Figure 45-1).

After ruling out DIC and HIT, full anticoagulation with intravenous heparin needs to be instituted. A bolus is usually not required. The recommended goal is 1000 units of heparin per hour, maintaining a PTT 2 to 2 1/2 times the normal value.

Treatment of most postoperative DVTs, regardless of other coexisting risk factors, consists of anticoagulation for 3 to 6 months. Transition to warfarin therapy should be undertaken while the patient is on heparin to prevent further clotting or skin necrosis by the reduction of proteins C and S by warfarin. In the subset of patients with malignancy, there may be a trend toward increased survival with the continued use of LMWH.^{34, 35, 36} The current recommendation is to continue anticoagulation as long as the cancer is active.³⁷

The challenge is to correct these defects rapidly in order to provide invasive brain monitoring. The amount of FFP needed to correct these defects of PT and PTT is excessive. Ten milligrams of IV vitamin K would not be sufficient to lower the INR. Furthermore, it is important to remember that patients with liver failure have inhibited production of clotting factors, as well as the procoagulant proteins C and S. Measuring levels of these proteins takes significant time and therefore is not feasible in management of acute fulminant hepatic failure with both ICP crisis and active bleeding.

This is a setting in which PCCs can be effectively used. They contain factors II, VII, IX, and X, which are deficient and needed for hemostasis. Some guidelines recommend the use of FFP along with PCCs as it provides factor V needed for hemostasis, as well as providing an increased amount of factor VII.³⁸

A variety of PCCs exist around the world, and a dosage of 50 units/kg is often recommended for life-threatening bleeding disorders. These products are virally inactivated and are not known to transmit hepatitis A, B, or C or HIV. PCCs can be rapidly infused in small volumes, work immediately, and can frequently reverse the INR and PTT to levels acceptable for the surgery and invasive procedures. As patients with liver disease frequently have platelets that are qualitatively abnormal, treatment with desmopressin (DDAVP, 0.3 μg/kg; see Table 46-2) is recommended as well.

The occurrence of thrombocytopenia in an ICU setting is common. The etiology of thrombocytopenia is multifold. Common etiologies for thrombocytopenia include sepsis, use of ventricular-assist devices, and medication induced. Given the clinical scenario, the most likely diagnosis in this case is heparin-induced thrombocytopenia. Thrombocytopenia is a well-established complication of heparin therapy.

There are two forms of thrombocytopenia associated with heparin therapy (Table 46-4). The first (type I) is a nonimmune form in which there is a moderate decrease in platelet count a few days after heparin initiation.³⁹ Type I HIT is not thought to be immune mediated. The second (type II) is the most important form of thrombocytopenia associated with heparin and is the focus of this chapter. Type II HIT, which we now refer to as HIT, is an immune-mediated reaction to heparin due to antibodies against the heparin/platelet factor 4 complex.⁴⁰ These antibodies lead to the activation of platelets, and subsequently the coagulation system, and may cause thrombosis and thrombotic multisystem complications.

Clinical features of HIT that help differentiate it from other causes of thrombocytopenia include the timing of onset, the degree of thrombocytopenia, and the presence of thrombosis. A scoring system is in use that helps assess the pretest probability of HIT. Clinical judgment must guide the diagnosis of HIT, as HIT testing results can take days to return.

Factors associated with an increased likelihood of the development of HIT include the following^{41, 42, 43}:

• Use of unfractionated heparin more than LMWH

• Surgical more than medical patients

• Female more than male patients

It is important to recognize that HIT can occur in the setting of intravenous heparin therapy, subcutaneous heparin therapy, and heparin flushes.

HIT Assay Testing

Running a HIT assay can take time, and therefore treatment decisions are not based on test results. Laboratory testing for HIT falls into the category of either immunologic or functional assays. Immunologic tests, which are more readily available, assess for the presence of antibodies against the platelet factor 4/heparin complex but cannot assess their capacity to activate platelets. Functional assays assess the capacity of antibodies to activate platelets. However, this testing is not widely available and results may take many days. Therefore, the functional assays serve to merely confirm the diagnosis.

Treatment of HIT

One must make sure that all forms of heparin, including flushes, have been discontinued. As these patients continue to be at risk for thrombosis after the heparin is stopped, alternative anticoagulation should be initiated. Two nonheparin, direct thrombin inhibitors are approved for use in the United States.

Warfarin should then be initiated when the platelet count is greater than 150,000, with a 5-day overlap between treatment with an alternative anticoagulant and warfarin therapy. In a patient with HIT-associated thrombosis, anticoagulation should be continued for 3 to 6 months. In a patient with HIT but no evidence of thrombosis, the appropriate length of anticoagulation is unclear, but anticoagulation for at least 1 month should be considered. For every patient the risk-benefit of anticoagulation should be taken into account.

An increasing number of patients who have been taking chronic antiplatelet agents present to the ED with acute bleeding. Retrospective analyses suggest that prehospital antiplatelet therapy in trauma patients is associated with increased morbidity and mortality rates.^{44, 45} Reversal of these agents can be complex. The antiplatelet effect of aspirin is mediated by inhibition of cyclooxygenase 1 (COX-1) in platelets. Aspirin irreversibly inhibits COX-1 through protein acetylation.⁴⁶ Therefore, this effect lasts for the life of the platelets, which is approximately 5 to 10 days, after which a sufficient number of new platelets would be in systemic circulation.

DDAVP is a vasopressin analogue that increases release of von Willebrand factor and associated factor VIII from endothelial storage sites.⁴⁷ DDAVP may help overcome aspirin-induced platelet dysfunction and ameliorate hemostasis^{48, 49} based on retrospective and small case control studies.

DDAVP is known to improve hemostasis in von Willebrand disease and hemophilia,⁴⁷ as well as improving the acquired platelet dysfunction found in uremic or cirrhotic patients.⁵⁰ The usual dose of DDAVP is 0.3 μg/kg in 50 mL of normal saline administered over 30 minutes (a maximum of 20 μg is recommended). It works almost immediately. As DDAVP is a vasopressin analogue, it has antidiuretic properties, and hyponatremia can result after repeated dosing. Serum sodium must be monitored. A lower dose (0.15 μg/kg) is advised for patients with significant cardiovascular disease.

Platelet transfusion can also be used in this setting, as transfusion will provide normal platelets as long as aspirin is no longer in the system. Case reports in the literature also report successful use of DDAVP in clopidogrel-induced platelet dysfunction, as well as in patients on combination therapy, although there is not enough evidence to support this finding.

In order to ascertain which patients on aspirin and clopidogrel are at true risk for bleeding, rapid platelet-specific tests are available in certain institutions. Historically the bleeding time was used, but this test has fallen out of favor due to poor reproducibility of results. In place of bleeding times, platelet function tests are now used. These tests can assess the qualitative platelet dysfunction, and their use is spreading. They can rapidly provide valuable information about the degree of platelet inhibition occurring in a patient on aspirin or clopidogrel.^{51, 52} These tests can be particularly helpful in cases where the antiplatelet medication history is unclear, or in the setting of vague history while surgery and an invasive procedure are urgently indicated.