Massive Transfusion, Bleeding and Coagulation Disorders in the ICU (Review)

Because coagulopathies (an impairment of blood clotting), thrombotic states, and bleeding are all interrelated through the coagulation cascade, and because they occur often in critically ill patients, it makes sense to consider these bleeding and clotting disorders together.

Don't correct coagulopathies in critical illness unless there is a specific reason (e.g., bleeding or an upcoming invasive procedure).

Massive Transfusion in the ICU

There is little evidence to guide the use of blood products in the ICU. With the realization that transfusion of blood products can cause harm, the historical tendency to "physiologically" correct hemoglobin and coagulation factors toward normal has been supplanted by a more cautious, restrictive approach, in general.

For patients with major bleeding after trauma ("massive transfusion," >10 units pRBC / 24 hours):

How much fresh frozen plasma should be transfused for each unit of packed red cells? No one knows. A large randomized trial, PROPPR showed no difference between varying ratios. Retrospective series of military and civilian casualties suggested a 1:1 ratio of FFP to pRBC improved survival, and have led to adoption of these ratios (1:1 or 1:2 FFP to RBC) both in massive and non-massive transfusion. However, these studies were methodologically flawed by survival bias and heterogeneity, and there may be risks to the approach. In one study, patients receiving such a "high FFP" strategy for non-massive transfusions (<10 units pRBC / 24 hours) had 12 times the incidence of ARDS (conceivably due to transfusion-related lung injury or TRALI). Europeans tend not to use FFP at all, preferring to use thromboelastometry to guide factor concentrate infusions (prothrombin complex, factor VIII, fibrinogen). These principles apply to patients with major trauma; applying them to massive GI bleeding has not been tested. When and how should tranexamic acid (TXA) be used in massive transfusion? All patients with major bleeding after trauma should receive tranexamic acid as soon as possible, according to experts' interpretation of the CRASH-2 trial in which TXA reduced mortality by 1/3, in patients who received the drug within 3 hours after injury. The use of tranexamic acid in severe gastrointestinal hemorrhage is being studied now in the HALT-IT randomized trial. How should fibrinogen be used in massive transfusion? Fibrinogen should be supplemented to 1.5 - 2.0 g/dL (150-200 g/L) in massive transfusion, according to European guidelines; this is expert opinion not supported by randomized trial data.

Correcting Coagulopathies Before Invasive Procedures and Surgery

No good evidence exists to support the practice of transfusing fresh frozen plasma to correct laboratory abnormalities in coagulation parameters prior to invasive procedures or surgery. Abnormal clotting tests before procedures do not predict subsequent bleeding accurately. Physicians nevertheless correct coagulopathy routinely before procedures, with significant variation in lab value (e.g. INR) thresholds triggering FFP transfusion. This author suggests an INR of 1.5 or less is appropriate for placement of a central line or arterial catheter. Other authors have suggested an INR of <2.5 is suitable for many commonly performed invasive procedures. including central lines (but not arterial puncture). Experts endorse giving vitamin K 1 mg orally daily or 10 mg IV weekly to ICU patients at risk for bleeding, because many are deficient.

Disseminated Intravascular Coagulation (DIC) in the ICU

Disseminated intravascular coagulation is “an acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes.” Both pro- and anti-coagulation factors are consumed, along with platelets. DIC most often results from sepsis, but widely variable in its severity and manifestations, from low-grade coagulating abnormalities to (rarely) overwhelming organ failure as in menigococcal sepsis. Profuse hemorrhage from DIC is unusual, although oozing at puncture sites is common. Microthrombi, but not large vessel thrombi, are common. Management of DIC is guided by local custom and expert opinion, which suggests observing abnormal coagulation factors, except in patients who are bleeding:

• Transfuse platelets to >50,000/mm³

• Fresh frozen plasma to INR < 1.5

• Fibrinogen (e.g. in cryoprecipitate) to >1.5 g/dL (150 g/L)

Experts advise not giving antithrombotic therapy such as heparin, even in patients with a "thrombotic phenotype" like gangrene (a suggestion based on physiology rather than outcomes data).

Thrombocytopenia in the ICU

Thrombocytopenia occurs in 20-40% of medical/surgical patients in ICUs, and its cause is usually impossible to identify. The important thing is to rule out heparin-induced thrombocytopenia (HIT) and thrombotic thrombocytopenic purpura (TTP), two diagnoses that threaten life and limb, and are treatable.

Because of the high false positive rates of HIT assays, reserving them for patients with higher pretest probability for HIT improves their performance. Experts advise using the 4Ts method for this.

For stable, non-bleeding patients, transfuse to platelets > 10,000 / mm³. In most bleeding patients, transfuse to >50,000/mm³. In those bleeding into the central nervous system (or at risk) or for neurosurgery, transfuse to 100,000/mm³, expert opinion advises.

If there is suspicion for thrombotic thrombocytopenic purpura, ask the lab or your hematologist to look for fragmented red cells (schistocytes) on peripheral blood smear. TTP usually causes very low platelet counts (<20K), and does not typically elevate the prothrombin time (INR), helping to distinguish it from DIC. Prompt recognition and plasmapheresis can dramatically improve the 95% mortality rate of untreated TTP.

Iatrogenic Bleeding in the ICU: Reversal Agents

The newer antithrombotic drugs (dabigatran, rivaroxaban, et al) have no proven effective reversal agent (antidote). Prothrombin complex concentrate may be effective, moreso for rivaroxaban than for dabigatran. Oral activated charcoal can be given in the rare cases of a presentation within 2 hours of ingestion. Drug How it Works Half-Life Cleared By Reversal Agent Heparin (UFH) Antithrombin III activation (anti-Xa) 60-90 min Cells mostly; kidneys at high doses Protamine 25-50 mg slow IV (1 mg/100 U heparin) Enoxaparin (Lovenox, LMWH) Same (anti-Xa) 4-6 hrs Kidneys Protamine about 60% effective Warfarin (Coumadin) Vitamin K antagonist reduces factors II, VII, IX, X Varies by patient Liver Vitamin K (1-5 mg IV), prothrombin complex concentrate (1000-2000 U) better than FFP Aspirin COX inhibitor, inactivates platelets Hours, but... ...effects persist until new platelets are made Platelet transfusion; consider DDAVP Clopidogrel (Plavix et al) Binds to P2Y12 ADP receptors on platelets, inactivates them Hours, but... ...effects persist until new platelets are made Platelet transfusion; consider DDAVP Fondaparinux (Arixtra) anti-Xa ~18 hrs Kidneys No known antidote; consider NovoSeven for severe bleed Dabigatran (Pradaxa) Direct thrombin inhibitor ~15 hrs Mostly by kidneys No known antidote; consider hemodialysis, prothrombin concentrate, NovoSeven Rivaroxaban (Xarelto) Direct factor Xa inhibitor ~8 hrs Liver and kidneys No known antidote; consider hemodialysis, prothrombin concentrate, NovoSeven Argatroban (Acova) Direct thrombin inhibitor < 1 hour Liver No known antidote Bivalirudin (Angiomax) Direct antithrombin actions < 1 hour 80% enzymatic breakdown; 20% kidneys No known antidote; consider hemodialysis or plasmapheresis for severe bleed Danaparoid Heparin-like effects ~1 day Kidneys No known antidote; consider plasmapheresis PROPPR Trial, JAMA, 2015 Beverley Hunt. Bleeding and Coagulopathies in Critical Care. N Engl J Med 2014;370:847-59. DOI: 10.1056/NEJMra1208626 Rice TW. Coagulopathy in critically ill patients: part 1: platelet disorders. Chest 2009. Wheeler AP. Coagulopathy in critically ill patients: part 2-soluble clotting factors and hemostatic testing. Chest 2010. American Society of Hematology: Reversal of Anticoagulation Guidelines 2011. EMCrit: Reversal of Anti-coagulant and Anti-platelet Drugs in Head Bleeds [podcast]