Hemorrhagic Risk and Blood Components
Allen Hamdan
Amy Evenson
Introduction
Although surgeons often rely on the expertise of pathologists, hematologists, and blood bank personnel, some of the subtleties regarding use of blood components are critical to a surgeons’ complete care of the patient. Therefore, it is important to have an understanding of the basics of hemostasis, the clotting cascade, and fibrinolysis, as well as common disorders and coagulation abnormalities that may be encountered. In addition, it is crucial to understand the risks and benefits of transfusion therapy, the complications of said therapy, and particular situations where issues may be expected to occur. Finally, a description of heparin-induced thrombocytopenia and the use of new anticoagulants are provided.
It is accurate to state that many surgeons take for granted the safety of the U.S. blood supply, but lessons learned in other countries are illustrative. Approximately 80% of the world’s population has access to only 20% of the safe blood supply. For instance, in places such as Latin America, where donations are often non-altruistic (i.e., done for livelihood purposes), infection with human immunodeficiency virus (HIV) and hepatitis is not uncommon. Transfusion of unsafe blood products accounts for up to 16 million hepatitis B, >4 million hepatitis C, and 160,000 HIV infections per year. Up to 20% of donated blood is not tested for transmissible infections and 25% of maternal deaths can be linked to blood loss and incumbent issues related to the blood supply.
It is clear from studies that paid donors are more likely to conceal information about risky behavior. In a number of countries, achieving a donor base that is at least 50% altruistic is a difficult target to reach. The Pan-American Health Organization funded by the Gates Foundation, has attempted to ensure that the region’s blood supply is screened for hepatitis and HIV, as well as other endemic problems such as Chagas disease. In addition, centralized blood collection systems have obvious advantages over small or local banks.
An episode from 2002 in this country is illustrative of potential problems even when the blood is extensively tested. There are new viruses that become endemic and especially if the time from incubation to development of disease is long (Creutzfield-Jacob), identification and screening can be difficult. In 2002, about 4,200 people were infected with mosquito-borne West Nile virus. During this time, there were 23 cases of transfusion-transmitted infection and seven related deaths due to this virus, which was obviously not screened at that time. Soon after, nucleic acid amplification technology was adapted for detection of this virus and the threat was essentially removed. Current screening practices include review with the potential donor of risk factors as well as history of transmittable infectious disease such as hepatitis C and B, HIV 1 and 2, HTLV I and II, malaria, babesiosis, and Chagas disease. Blood is also screened for indications of underlying infection.
Although most surgeons view hemostasis as the appropriate suture and knot, clear knowledge of the clotting cascade is critical. It is very important to understand the types of factors or blood products that should be administered at any given time and what the potential issues/contraindications may be. Since each product ordered from the blood bank carries some risk, at least a basic facility with their uses is expected. Part of the overall care of the patient is based on the evaluation of preexisting “bleeding” disorders as well as those that may be acquired from complications related to surgery or new underlying disease processes. Finally, understanding the use and/or complication of the omnipresent heparin (mainly related to heparin-induced thrombocytopenia), as well as the myriad novel anticoagulants is part of excellent surgical care.
Components of Normal Hemostasis
Hemostasis relies on a dynamic, minute-by-minute interactive process between platelets and coagulation complexes. When cells are injured, tissue factor (TF) is released and this activates the extrinsic pathway. This damage of the endothelium of blood vessels exposes the underlying collagen to platelets and thus, activates them. In the blood, tissue factor forms a complex with activated Factor VIIA. This complex subsequently activates IX and X. At the same time, stimulated platelets change their shape, externalizing among other enzymes, the procoagulant phospholipid platelet factor 4 (PF4). Coagulation proteins can thus, assemble on the surface of the platelets allowing acceleration of coagulation reactions. Dormant platelets do not express binding sites for coagulation factors. von Willebrand factor (vWF) is responsible for platelet adhesion by binding to glycoprotein IB. Fibrinogen forms bridges between platelets by binding to glycoprotein IIB/IIIA and adjacent stimulated platelets. This leads to a platelet plug being formed. Factor Xa can now activate Factor V. Ionized calcium and prothrombin now complex on the platelet lipid surface to initiate the catalyzation that leads to the formation of thrombin.
All coagulation, regardless of whether it is related to extrinsic or intrinsic pathway requires thrombin. Thrombin, among other things, acts to cleave fibrinopeptide A from the alpha chain of fibrinogen and fibrinopeptide B from the beta chain. This release of fibrinopeptides allows formation of fibrin monomers, which cross-link. Thrombin, in addition, activates Factor XIII, which affects a number of coagulation processes. These include acceleration of cross-linking of fibrin to make the clot harder, activation of platelets, as well as Factors V and VIII. It also cross-links other plasma proteins such as fibronectin and incorporates them into the clot. What is apparent is that many complexes/mechanisms are interacting at a given time, but derangement of just one key component can lead to disastrous problems.
The intrinsic pathway basically requires the formation of XIa from XI. This involves changes on the vascular surface and starts with XIIa converting XI to Xia, which in turn converts IX to IXa. The combination of IXa, X, calcium, and VIIIa on the platelet surface forms the x-ASE complex, which then catalyzes the conversion of Factor X to Xa. The process can occur by the contact activation system with Factor XII and prekallikrein, and also by thrombin’s interaction with negatively charged surfaces. There are multiple overlaps and amplification steps, partly based on autocatalytic nature of certain factors. The remainder of the pathway follows along with the extrinsic mechanisms.
To understand the extrinsic pathway, the critical role of tissue factor or thromboplastin needs to be delineated. Tissue factor is an integral membrane glycoprotein that is not typically expressed on vascular endothelial cells, but is noted on skin, vascular adventitia, and organ surfaces. Typically, tissue factor is exposed to flowing blood only after endothelial damage. Cell lysis leads to activation of tissue factor, which is normally in a dormant state. It may also circulate in the blood in microvesicles, typically of stimulated macrophages. These microvesicles can then fuse with and initiate coagulation-activated platelets. The end product of TF’s interactions, which are complex, is activated Factors X and IX. Since Factor X is at the center of all coagulation reactions, it is critical that both pathways lead to the production of Xa. This is made even more apparent if one focuses on the extrinsic pathway alone, since the amount of TF generated is fairly limited, partly due to the presence of tissue factor pathway inhibitor.
Control Mechanisms and Termination of Clotting
For any organism to have the ability to have flowing blood, heal wounds, and stop bleeding, as stated above, a very intricate set of checks and balances needs to be in place. If hemostasis, which is part of wound healing and tissue remodeling, was allowed to go unfettered, patients would not survive after any injury. Thus, innate pathways have been developed to aid in both clot elimination and fibrinolysis. In addition, these are changing second by second at a molecular level and do not just remain stagnant until some event such as a trauma occurs. Antithrombin, heparans, activated protein C and S, and tissue plasminogen activator (TPA) are a few of the critical factors involved in halting further clot, its elimination, and eventual fibrinolysis.
Antithrombin is circulating plasma protease inhibitor with two functional sites, a so-called reactive center and heparin-binding site. It forms equimolar irreversible complexes with a majority of enzymes in the clotting cascade including thrombin, Xa and IXa. The binding of endogenous or exogenous heparins or heparans to the active site produces a conformational change. The glycosaminoglycans heparan sulfate is found naturally on endothelial surfaces and contains a critical pentasaccharide that in part mediates the physiologic action of antithrombin. This allows the endothelial cells to have already activated antithrombin on their surface allowing destruction of excess thrombin in the general circulation.
Activated protein C (APC) joins with protein S on phospholipid surfaces and causes the proteolysis of Factors Va and VIIIa. Of note, protein S functions to amplify the effects of activated protein C. This is critical because this complex inactivates both prothrombinase and the intrinsic X-ase. Elucidation of the importance of APC can occur with understanding of the hematologic condition, Factor V Leiden, in which the arginine in Factor V is replaced by glutamine, thus making it not susceptible to cleavage by activated protein C. This leads to promotion of a potentially hypercoagulable state. When heterozygous, this can be “dormant,” until one develops an inflammatory state (infection, trauma, and surgical injury) in which the acute phase reactant C4B-binding protein (compliment system) is increased. Since this binds freely circulating protein S, the likelihood of thrombosis is enhanced.
Protein C and S primarily function as circulating anticoagulants; thus, as will be described further in this chapter, they become critical during periods when thrombosis exceeds fibrinolysis. This can be seen in a number of scenarios but it is easy to understand when you note that Coumadin, the most widely used anticoagulant, is initially a procoagulant since it inhibits protein C and S (short half-life) before it effects the clotting cascade factors. This is one of the main reasons patients with active heparin-induced thrombocytopenia should not receive Coumadin until they are fully anticoagulated with direct thrombin inhibitors (DTIs).
Plasminogen, a precursor to plasmin, forms a ternary complex with fibrin and TPA. This leads to generation of a very active proteolytic plasmin, which destroys fibrin, fibrinogen, and a number of other plasma proteins and clotting factors. When plasmin is active, it leads to release of fibrin degradation products; this is what is measured in the D-dimer laboratory test. TPA itself is an endothelial cell enzyme that circulates as a complex with its inhibitor plasminogen activator inhibitor one (PAI-1). TPA recognizes lysine residues on the fibrin clot and when it binds, this aligns TPA with plasminogen directly on the fibrin surface making its efficacy increase exponentially. Urokinase is also a plasminogen activator and, whereas TPA initiates and continues intravascular fibrinolysis urokinase functions
mainly in the extravascular space. PAI-1 is made both by platelets and endothelial cells. In those deficient in PAI-1 significant bleeding can develop when the normal mechanisms are overwhelmed by things such as trauma. It is aggressively released by activated platelets and probably accounts for the fact that platelet-rich clots seen in arterial thrombus are much harder to lyse than the cell-poor thrombus noted in venous clots.
mainly in the extravascular space. PAI-1 is made both by platelets and endothelial cells. In those deficient in PAI-1 significant bleeding can develop when the normal mechanisms are overwhelmed by things such as trauma. It is aggressively released by activated platelets and probably accounts for the fact that platelet-rich clots seen in arterial thrombus are much harder to lyse than the cell-poor thrombus noted in venous clots.
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Many patients at risk for perioperative bleeding complications can be identified through the performance of a complete personal and family history and physical examination. Basic screening and confirmatory testing may be performed as indicated by findings on this initial evaluation. Appropriate perioperative management of patients with bleeding disorders depends on identifying those patients at risk and defining the defect in coagulation pathways that may be present.
Initial discussion with the patient centers on the occurrence of prior serious bleeding problems related to injuries, dental procedures, surgical procedures, or menstruation and childbirth in women. Of particular concern are episodes of spontaneous, excessive, or delayed in onset. A family history of bleeding episodes should be elicited, although a negative family history does not entirely exclude an inherited coagulation disorder due to the occurrence of spontaneous mutations and incomplete penetrance of certain conditions. Prior history of iron-responsive anemia or need for transfusions as well as history of thyroid, liver, or kidney disease may suggest a bleeding diathesis. Review of prescription and over-the-counter medications may also reveal patients at risk for perioperative bleeding. While prescription anticoagulants such as aspirin, clopidogrel, and Warfarin are well known to increase bleeding risk, many frequently used nonprescription medications, vitamins, and dietary supplements can also interfere with hemostatic mechanisms. Nonsteroidal anti-inflammatory agents, vitamin E, ginkgo biloba, ginseng, garlic, and echinacea have all been associated with an increased risk of bleeding. In addition, use of antibiotics may alter the gut flora metabolism of vitamin K while malnutrition or malabsorption may decrease the synthesis of vitamin K-dependent coagulation factors.
Physical examination help distinguish between disorders of platelet number and function versus a coagulation factor deficiency. Petechiae, superficial ecchymoses, mucocutaneous bleeding, and purpura are suggestive of platelet or blood vessel abnormalities, while deep tissue hematomas and hemarthroses implicate inherited defects in coagulation factors.
In the absence of identified risk factors, patients may proceed to minor procedures without formal laboratory evaluation of hemostatic parameters. General screening tests are recommended for more invasive procedures or in the setting of concerns raised on history and physical examination. Initial testing of platelet count, prothrombin time (PT), and activated partial thromboplastin time (aPTT) may identify some patients at risk for perioperative bleeding and distinguish between defects of platelets and coagulation factors. Peripheral blood smear will provide insight into platelet number and morphology. Bleeding time has long been recommended as a comprehensive test of platelet and blood vessel hemostatic functions, although it is not uniformly offered at all centers due to the resources involved in performing the test as well as variation in technical factors in performance of the test. The Platelet Function Analyzer (PFA-100) is a more standardized test of platelet function and is increasingly available. Prothrombin time tests for integrity of the extrinsic pathway and is used to monitor the effects of Warfarin. Due to variability in assays, the PT is usually reported as an international normalized ratio (INR). aPTT tests the intrinsic pathway of coagulation and is used to monitor heparin effects. An elevated aPTT may suggest heparin effect or deficiency of any factor, except VII and XIII. Concern for deficiency of specific coagulation factors may be assessed by testing for specific factors or factor inhibitors. Fibrinogen activity may be measured while testing for abnormal fibrinolysis and is assessed by measuring fibrin and fibrinogen degradation products (FDP). Measurement of D-dimers reflects presence of clot as breakdown of previously cross-linked fibrin is required. Findings of the various tests of coagulation are described with the disorders described below.
Common Coagulation Disorders
Acquired bleeding disorders are much more common than congenital deficiencies in coagulation. A review of common bleeding disorders serves to outline the use of preoperative screening and diagnostic testing as well as appropriate management to minimize morbidity and mortality following surgical procedures. Management of these uncommon conditions should be undertaken in a multidisciplinary approach including hematologists and blood bank physicians for optimal outcomes.
Congenital Disorders of Platelets and Coagulation Factors
Congenital defects of platelet number and function are rare. A history of abnormal bleeding and easy bruisability is often present with abnormal tests of platelet function (bleeding time or PFA-100) discovered on evaluation. Glanzmann thrombasthenia is an autosomal recessive disorder resulting in an abnormal glycoprotein IIb/IIIa receptor that prevents platelet clumping. Treatment with platelet transfusion or recombinant Factor VIIa may be required for hemostasis. Bernard-Soulier syndrome results from a defect in the glycoprotein Ib–IX complex that prevents platelets from adhering to blood vessel walls. Storage pool disorders refer to specific deficiencies within platelet granules that result in poor platelet aggregation. One such example is Wiskott-Aldrich syndrome, an X-linked recessive disorder that is also associated with immunodeficiency. Other storage pool disorders include Chediak-Higashi syndrome, Hermansky-Pudlak syndrome, and thrombocytopenia-absent radius syndrome. Platelet transfusion is often required but may result in production of antihuman leukocyte antigen antibodies or antibodies to the missing receptors, resulting in rapid destruction of the transfused platelets.
von Willebrand disease (vWD) is the most common inherited bleeding disorder and results from defects in vWF, a glycoprotein responsible for platelet adhesion to vascular subendothelium as well as carriage of Factor VIII. Multiple subtypes have been identified with variable clinical presentation. Type I is the most common form, resulting in a decreased quantity of vWF. Type II vWD results from an abnormal configuration of the glycoprotein. Type III is the most severe form with essentially no vWF activity. Type I vWD responds to administration of DDAVP, while types II and III require cryoprecipitate or Factor VIII replacement.
Clinically important deficiencies of most factors in coagulation have been reported. The most common disorders are hemophilia A and B resulting from defects in Factors VIII and IX, respectively. Both forms of hemophilia are X-linked recessive disorders with up to 20% of cases representing spontaneous mutations with no prior family history. Percent of factor level present determines the severity of presentation with severe cases associated with <1% activity,
moderate cases with 1% to 5% activity, and mild cases with 5% to 50% activity. Severe cases manifest spontaneous hemorrhage in joints, muscles, and soft tissues; moderate cases have less spontaneous bleeding but may have prolonged bleeding after trauma or surgery; and mild cases are often not suspected until bleeding occurs after invasive procedures. Both forms of hemophilia present with normal platelet counts, normal PT/INR, and prolonged aPTT; reduced factor levels are discovered on further testing. Treatment with specific factor concentrates or fresh frozen plasma (FFP) is required to prevent bleeding during and after procedures. Mild cases of hemophilia A may also be treated with DDAVP, which causes the release of Factor VIII into the circulation. Specific formulas are available to guide dosing of replacement therapies in the perioperative setting. Correction of factors must be maintained in the postoperative setting to avoid delayed onset of bleeding.
moderate cases with 1% to 5% activity, and mild cases with 5% to 50% activity. Severe cases manifest spontaneous hemorrhage in joints, muscles, and soft tissues; moderate cases have less spontaneous bleeding but may have prolonged bleeding after trauma or surgery; and mild cases are often not suspected until bleeding occurs after invasive procedures. Both forms of hemophilia present with normal platelet counts, normal PT/INR, and prolonged aPTT; reduced factor levels are discovered on further testing. Treatment with specific factor concentrates or fresh frozen plasma (FFP) is required to prevent bleeding during and after procedures. Mild cases of hemophilia A may also be treated with DDAVP, which causes the release of Factor VIII into the circulation. Specific formulas are available to guide dosing of replacement therapies in the perioperative setting. Correction of factors must be maintained in the postoperative setting to avoid delayed onset of bleeding.
Spontaneous and postprocedure bleeding due to abnormal fibrinolysis has been described. Absence or abnormalities of fibrinogen, plasminogen activator inhibitor-1 (PAI-1) deficiency, and alpha-2-antiplasmin deficiency may all lead to prolonged bleeding. The diagnosis and management of these disorders is beyond the scope of this text and consultation with experts in hematology is advised in managing patients with these conditions in the perioperative setting.
Acquired Disorders of Platelets and Coagulation Factors
Qualitative and Quantitative Platelet Deficiencies
Numerous medications and medical conditions may decrease the number or function of platelets. Therapeutic antiplatelet agents are in wide use for their cardiovascular and anticoagulation effects. Aspirin, clopidogrel, nonsteroidal anti-inflammatory drugs, dipyridamole, and GP IIb/IIIA antagonists (abciximab, eptifibatide) all induce thrombasthenia by altering the ability of platelets to aggregate. Combination therapy using multiple antiplatelet agents together or with Warfarin is common and worsens bleeding complications. In addition to direct inhibition of platelet function, many medications are associated with thrombocytopenia via predictable or idiopathic mechanisms. Cephalosporins, penicillin, H2-antagonists, digoxin, amiodarone, furosemide, phenytoin, and tricyclic antidepressants are all commonly used medications that can cause thrombocytopenia. Heparin-induced thrombocytopenia (discussed elsewhere in this chapter) is a growing cause of morbidity and mortality in medical and surgical patients.
Uremia is associated with increased bleeding due, at least in part, to platelet dysfunction. This dysfunction is thought to be multifactorial and include abnormal glycoprotein expression, platelet granule function, and prostaglandin and thromboxane metabolism in combination with uremic toxins, anemia, and abnormal endothelium. Dialysis to correct uremia and administration of 1-deamino-8-D-arginine vasopressin (DDAVP) are both recommended to counter altered platelet function in renal failure. Liver disease has a multitude of effects on the coagulation system (see below) including platelet function and number. Acute hepatitis may cause transient thrombocytopenia while cirrhosis may lead to portal hypertension, hypersplenism, and resultant thrombocytopenia. Qualitative defects in platelet aggregation are also seen in chronic liver disease. Immune-mediated thrombocytopenic purpura, thrombotic thrombocytopenia purpura, and systemic lupus erthematosus also commonly cause decreased platelet counts. Treatment of these etiologies of thrombocytopenia may include platelet transfusion, steroids, or splenectomy depending on the clinical circumstances and presence of bleeding.
Disorders of Coagulation Factors and Mixed Abnormalities
Acquired deficiency of vitamin K leads to poor carboxylation of Factors II, VII, IX, and X. Vitamin K is found in green, leafy vegetables and in synthesized by gut flora. Deficiencies can occur in malnutrition or malabsorption, alteration of gastrointestinal flora after antibiotic use, and during Warfarin therapy. Low levels of vitamin K-dependent factors are reflected in an elevated PT/INR. Bleeding due to an elevated PT/INR due to vitamin K deficiency may be corrected quickly with FFP, or more slowly with administration of oral or subcutaneous vitamin K. Intravenous administration of vitamin K may result in allergic-type reactions, although the actual number with current purified micellar preparations is exceedingly low. Current recommendations of The American College of Chest Physicians (2008) are as follows: “For the use of vitamin K to reverse a mildly elevated INR, we recommend oral rather than subcutaneous administration (Grade 1 A). For patients with life-threatening bleeding or intracranial hemorrhage, we recommend the use of prothrombin complex concentrates or recombinant Factor VIIa to immediately reverse the INR (Grade 1 C).”
Acquired inhibitors of many coagulation factors have been described. The most common of these acquired inhibitors are Factor VIII inhibitors. Patient with hemophilia A may develop antibodies due to repeated exposure to exogenous Factor VIII. Other risk factors for development of anti-factor VIII antibodies include pregnancy, rheumatoid arthritis, malignancy, medications, and systemic lupus erythematosus. Bleeding may be spontaneous or following tissue trauma and is often severe. Initial testing demonstrates a prolonged aPTT while inhibitor screening via mixing tests are required to identify the presence of an inhibitor. The Bethesda assay confirms presence of Factor VIII inhibition through the use of serial dilution of patient plasma. Treatment of Factor VIII inhibition requires immunosuppression using prednisone, cyclophosphamide, intravenous immunoglobulin, or plasmapheresis to remove the antibody. Administration of DDAVP and exogenous Factor VIII at high doses may overcome the inhibitor; recombinant factor VIIa may be required in cases with high titers or significant bleeding. Antibodies to prothrombin, thrombin, and Factors V, VII, IX, X, XI, and XIII have been described. Treatment for these disorders includes administration of FFP or factor concentrates if available; immunosuppression may also be required to suppress or remove the antibody.
Chronic liver disease results in multiple defects in coagulation. All factors except Factor VIII and vWF are produced by the liver including the vitamin K-dependent Factors II, VII, IX, and X. As described above, portal hypertension resulting from cirrhosis leads to hypersplenism and thrombocytopenia as well as qualitative defects in platelets. Coagulopathy of liver disease is multifactorial and may be reflected in elevated PT/INR and decreased platelet counts and function. Management of bleeding in patients with chronic liver disease often requires administration of platelets, FFP, vitamin K, and modulation of portal hypertension with pharmacologic agents (octreotide, vasopressin) or hemodynamic maneuvers (transjugular intrahepatic portosystemic shunting).
Massive transfusion related to traumatic injury results in multiple perturbations of the coagulation system. Dilution of platelets and clotting factors is uncommon outside of large-volume resuscitation, often defined as more than 10 units of blood or replacement of the entire blood volume within 24 hours. Administration of FFP, cryoprecipitate, and platelets can generally
be guided by results of platelet counts, PT/INR, aPTT, and fibrinogen levels. In significant trauma, data suggest that administration of red blood cells, FFP, and platelets at a ratio of 1:1:1 results in a survival benefit. Other factors to consider include hypothermia due to patient exposure and administration of cold products: increasing ambient temperature, active warming of infused products, and extracorporeal rewarming to maintain normothermia will improve coagulopathy. Acidosis from poor tissue perfusion will also worsen coagulopathy. Principles of damage-control laparotomy address these issues and call for minimal surgical procedure (i.e., stapling bowel to control fecal spillage, packing for hemostasis, and temporary abdominal closure) and active resuscitation with warming, correction of acidosis, and support of coagulation parameters in the intensive care unit prior to definitive surgical management.
be guided by results of platelet counts, PT/INR, aPTT, and fibrinogen levels. In significant trauma, data suggest that administration of red blood cells, FFP, and platelets at a ratio of 1:1:1 results in a survival benefit. Other factors to consider include hypothermia due to patient exposure and administration of cold products: increasing ambient temperature, active warming of infused products, and extracorporeal rewarming to maintain normothermia will improve coagulopathy. Acidosis from poor tissue perfusion will also worsen coagulopathy. Principles of damage-control laparotomy address these issues and call for minimal surgical procedure (i.e., stapling bowel to control fecal spillage, packing for hemostasis, and temporary abdominal closure) and active resuscitation with warming, correction of acidosis, and support of coagulation parameters in the intensive care unit prior to definitive surgical management.
Disseminated intravascular coagulopathy (DIC) represents a disordered state of microvascular thrombosis coupled with systemic fibrinolysis and subsequent hemorrhagic complications. Microangiopathic hemolysis may also occur due to microvascular thrombi and shear forces affecting red blood cells. Infections, injury, malignancy, trauma, burns, and obstetric complications may initiate DIC via exposure to procoagulant substances, thus stimulating diffuse thrombin and fibrin production. Coagulation factors and platelets are consumed while fibrinolytic mechanisms are also activated leading to diffuse bleeding. Laboratory abnormalities reflect consumption of factors and platelets with elevated PT/INR and aPTT, decreased fibrinogen and platelets, and evidence of fibrinolysis with elevated fibrin degradation products and D-dimer. Support with blood products is often required but resolution of DIC requires identification and treatment of the underlying cause. Multisystem organ failure may require supportive measures including intubation with mechanical ventilation, hemodynamic monitoring and support, dialysis for renal failure, antibiotics, and surgical debridement of devitalized tissue. In the absence of bleeding complications, some advocate for therapeutic heparinization to counter microvascular thrombosis, although data is lacking on this recommendation.
Heparin-Induced Thrombocytopenia
Heparin-induced thrombocytopenia was first described in 1962, just slightly <30 years after the institution of the clinical use of heparin. Sequelae of HIT, even though the syndrome involves development of a significant decrease in circulating platelets, rarely leads to hemorrhagic events, but predominantly causes venous thrombosis such as DVT and pulmonary embolism. It can less commonly lead to major arterial events, such as MI, stroke, and limb ischemia. The mortality rate can be as high as 30% to 50%. The incidence of HIT is highest with bovine heparin and unfractionated heparin (UFH) and less with low molecular heparin.
It is important to think of HIT as a syndrome that involves both clinical and serologic findings. One must differentiate between what some use as a “grab-bag,” the term in which patients develop a nonimmune system mediated and asymptomatic short-term drop in platelet count during heparin use—sometimes referred to as HIT type 1, in contradistinction to HIT type II or HITT (heparin-induced thrombocytopenia with thrombosis). For the true syndrome to occur, the patient will have a documented drop in platelet count plus or minus active acute thrombosis (venous or arterial), in addition to either identification of heparin-dependent antibodies or a positive Serotonin release assay (SRA). One, however, cannot make the mistake of minimizing the findings of decreased platelet count and positive antibodies but no current thrombosis. This may just reflect the early identification of the disease process and thrombosis may ensue over the next days to weeks.
Estimates vary, but up to 1 in 100 patients who receive UFH for 5 days or more will develop HIT. The culture of surgery and medicine has led to inappropriate and omnipresent use of heparin in patients in situations, where it is probably not needed, i.e., IV flushes and subcutaneous heparin in every patient who is in the hospital regardless of risk profile. This accounts for over 12 million patient uses and up to 1 trillion units administered per year. Especially in surgical patients, thrombocytopenia is common. However, this is most often due to platelet depletion with blood loss, not HIT. Although UFH is one of the most commonly used drugs as described above, even among surgeons there is lack of clarity of what is actually contained when the medication is injected. UFH is basically a very heterogeneous group of glycosoaminoglycans that can weigh anywhere from 3,000 to 30,000 Da and is made from animal sources. Low-molecular-weight heparin (LMWH), on the other hand, is a much more refined product derived from UFH by enzymatic processes, making it less heterogeneous, more uniform, and thus less antigenic. Part of the understanding of HIT is its prevention by avoiding heparin when it is not necessary. Familiarity with the American College of Chest Physicians consensus conference on DVT prophylaxis and use of heparin is important.
Pathogenesis
The centerpiece of the described events is PF4. PF4 is a positively charged protein found in all platelet alpha granules and on numerous cell surfaces, especially those of platelets and endothelial cells. Heparin molecules have a very high affinity for this molecule. How avid heparin is in relation to PF4 depends on the heparin chain link or molecular weight and its degree of glycation. This is the key reason that the larger UFH poses a higher risk than the smaller, more “pure” LMH.
After binding of exogenously delivered heparin to PF4, a conformational change develops and new epitopes are exposed leading to a generation of the classic heparin-PF4 antibodies. Once the antibodies are generated (usually IgG), they bind to the aforementioned heparin–PF4 complex. A somewhat complex multimolecular reaction then occurs in which platelets are activated via their FCY2 A receptors to discharge their microparticles leading to release of an additional significant amount of PF4. This condition, some describe as “platelet storm,” leads to ensuing platelet consumption with resultant thrombocytopenia and development of a nascent prothrombotic state. Interestingly, bleeding events even when platelet counts are <20 u/mL are rare. The platelet microparticles lead to excessive thrombin generation and thrombosis. In addition, the complexes can interact with monocytes leading to tissue factor production and then more antibody-mediated endothelial damage and clot production.
The frequency of development of heparin-PF4 antibodies depends on the patient population, the type of heparin, duration of therapy, and the antibody detection method. It is much more commonly seen in surgical patients, especially after cardiovascular procedures, when compared to medical patients. Bovine heparin also increase the risk compared to porcine heparin and it has also been clearly established that LMWH will produce these antibodies much less frequently than standard UFH, due to the smaller and more uniform heparin moieties.
It is also important to know that the development of the IgG against heparin/PF4 does not guarantee that the patient will progress to full-blown HIT. When aggressively sought out, antibodies will develop in up to 60% of patients undergoing cardiac surgical procedures, but the frequency of
true HIT is generally estimated to be 2.5%. A specific subcategory that shows an exceptionally high rate of HIT is in cardiac transplant recipients. Another somewhat contradictory finding is that although orthopedic patients are less likely to develop the antibodies than patients after CABG, as a general rule they are twice as likely as such patients to develop HIT. In general, there are a few explanations for the observation that antibodies plus platelet drop does not always equal thrombosis. The first relates to timing—the identification of the serology and lab abnormality can predate the development of thrombosis by days to weeks. Secondly, there may be subclinical thrombosis that develops and resolves such as a small tibial vein DVT. Finally, we have not been able to identity for sure which subset of patients will have the lab abnormalities and never develop thrombosis. Thus, the surgeon must be vigilant and the base treatment on factors detailed below does not consider this a minor problem or inconsequential lab abnormality.
true HIT is generally estimated to be 2.5%. A specific subcategory that shows an exceptionally high rate of HIT is in cardiac transplant recipients. Another somewhat contradictory finding is that although orthopedic patients are less likely to develop the antibodies than patients after CABG, as a general rule they are twice as likely as such patients to develop HIT. In general, there are a few explanations for the observation that antibodies plus platelet drop does not always equal thrombosis. The first relates to timing—the identification of the serology and lab abnormality can predate the development of thrombosis by days to weeks. Secondly, there may be subclinical thrombosis that develops and resolves such as a small tibial vein DVT. Finally, we have not been able to identity for sure which subset of patients will have the lab abnormalities and never develop thrombosis. Thus, the surgeon must be vigilant and the base treatment on factors detailed below does not consider this a minor problem or inconsequential lab abnormality.
General Recommendations/Findings
The “starting” platelet count is not the platelet count the night before heparin is instituted but the highest registered value over the prior 2 weeks. In addition, it is imperative to identify the potential use of heparin over the preceding 100 days, even if just administered as an IV flush, due to the amnestic response of a second dose.
DVT, PE, arterial occlusion, or combined arterial/venous thrombosis may be seen. In addition, it is easy not to consider as part of the complete spectrum of problems other manifestations such as skin lesions identified at the sites of heparin injection or anaphylactoid reactions that occur after heparin bolus. It is also important to note that in a sizeable number of HIT patients, the thrombotic event occurs days before the platelet count falls to levels that raise awareness and can significantly predate its diagnosis. The contrary is also true, further complicating matters. The other clinical scenario that can mask the identification of HIT is seen in patients being treated with UFH for a VTE. Later in their course when they develop progression of the thrombus, either with more proximal progression or a DVT identified at another site, this can be misdiagnosed as heparin failure but may in fact reflect development of HIT necessitating cessation of heparin and institution of a DTI.
Patients receiving UFH at therapeutic doses should have platelet counts monitored every 3 days until the heparin is stopped. In general, this does not apply to patients who are receiving intravascular catheter flushes. This, however, does not imply that patients who receive only small doses cannot develop HIT. Routine HIT antibody testing is not recommended in all patients who receive heparin outside laboratory signs or clinical findings that point to the potential diagnosis. In those patients with platelet counts falling by >50% and/or when a thrombotic event occurs within 2 weeks of heparin therapy (maximum 100 days), HIT should be suspected and evaluated.
Patients on Coumadin at the time of the diagnosis of HIT should be reversed with intravenous or oral vitamin K. This is to prevent the clinically relevant “hypercoagulable” state produced by the inhibition of Protein C and S. It is often first manifested by skin necrosis in patients given Coumadin. Reversal of course is only done when the patient is already fully anticoagulated by another appropriate measure such as the DTI Argatroban. This can be counterintuitive and easily missed. Platelet transfusions, although there has been recent evidence questioning this dogma, in the absence of significant active bleeding regardless of the nadir of platelet count, should not be given prophylactically. Since platelets are the key to activating and promoting the thrombotic nature of the syndrome, adding new platelets to the already deranged pathway can be disastrous and is usually done, incorrectly but in good faith, to treat the abnormal lab numbers.
General measures include cessation of all heparin products including flushes, reserving the use of platelets for emergencies, treatment with alternative anticoagulants plus or minus platelet inhibition with drugs such as Plavix. Other possible treatment modalities outside the scope of this chapter include plasmapheresis, which has an unproven role, but in small series may show decreased mortality rate if started very quickly, and high-dose intravenous gamma globulin given to suppress the heparin antibodies, which has been shown to be successful treatment in a few case reports.
Treatment of Hit
Patients with HIT should have their heparin stopped immediately and, in general, be treated with non-heparin anticoagulants including Danaparoid, Lepirudin, Argatroban, Fondoparinux, and Bivalirudin. Some of those drugs do not have indications for HIT in the United States and will be discussed with more specifics in the anticoagulant section. LMWH should never be considered a substitute even though it has a much lower rate of causing HIT. Daily platelet counts should be monitored looking for the nadir and eventual rise to above 150,000 or at least a stable new plateau. In addition, in those patients even without clinical signs, lower limb ultrasounds should be performed serially to identify occult DVTs. Although somewhat controversial, in patients with a negative venous duplex and no current thrombotic events or skin lesions, alternative anticoagulation should be strongly considered mainly for the fact that a significant percentage will “convert” and develop thrombosis when followed for several weeks. Obviously, prevention of potential thrombotic events has to be balanced by the risk of aggressive anticoagulation in early postoperative patients especially with agents that often do not have an “antidote.”
Warfarin therapy in general should not be instituted until the platelet count has substantially recovered to at least to a level of 150 × 10 9th/L. In addition, the non-heparin anticoagulant should be continued until the platelet count has reached a stable plateau, and INRs are in the appropriate target range. This generally results in a minimum overlap of at least 5 days.
Key Features and Potential Pitfalls of Identification and Treatment of Hit
Platelet count drop of >50%.
Platelet count typically <150 × 109/L but >20 × 109/L.
Platelet drop generally seen 5 to 15 days after initiation of dose.
Do not miss rapid onset in which the first and potentially small dose of heparin causes immediate drop in platelet count in those patients who have active antibodies from another recent heparin treatment—often a previous admission.
Another condition referred to as delayed onset HIT in which the platelet counts will drop more than 2 weeks after the heparin is stopped. Generally, the platelet drop is less severe.
Patients diagnosed with HIT without thrombosis at initial finding still have a >20% chance of developing thrombosis at a later date even after heparin cessation.
The risks still persist after the platelet counts return to normal, especially if a patient is not on a DTI.
Thrombosis can occur in either the venous or the arterial systems and in any location. The venous events are generally considered to be fourfold increased over arterial thrombosis.
Among patients with HIT and thrombosis, 10% will require limb amputation and are subjected to a mortality rate of up to 50%.Stay updated, free articles. Join our Telegram channel
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