Anticoagulant Therapy

Regulation of Hemostasis

July 23, 2017 Anticoagulant Therapy, Cardiology, Hematology, Physiology and Pathophysiology No comments , , , , , , , , , , , , , , ,

Key events that initiate and propagate coagulation are the redistribution of negatively charged phospholipids to the cell surface and the exposure of tissue factor to the blood. The appropriate negatively charged phospholipids, primarily phosphatidylserine, can arise as a result of either cellular activation with strong agonists like thrombin together with collagen in the case of platelets or tissue damage or death. The negatively charged phospholipids promote the activation of factor X and IX by the tissue factor-factor VIIa pathway, the activation of prothrombin by factors Va and Xa, and the activation of factor X by factors VIIIa and IXa. In addition, it has been suggested that oxidation of a specific disulfide in tissue factor is important for expression of its procoagulant activity, a process that may be regulated by protein disulfide isomerase, although this concept remains controversial.

Normally tissue factor is not present on cells in contact with blood. Tissue factor is found on extravascular cells surrounding the blood vessel so that a potent procoagulant surface is exposed when the endothelium is breached. This helps to seal the breach. Intravascularly, inflammatory stimuli can induce tissue factor synthesis and expression on leukocytes, particularly monocytes, providing a mechanism for the initiation of coagulation. This response likely contributes to disseminated intravascular coagulation (DIC). Animal studies suggest that this coagulation response plays a role in innate immunity and prevents the dissemination of infectious agents.

Other key events that can play a major role in the pathogenesis of thrombosis, at least in animal models, involve the release of intracellular components, including ribonucleic acid (RNA) and polyphosphates. These can trigger activation of factor XII, which initiates coagulation via the contact pathway. Although factor XII does not appear to contribute to hemostasis, it drives several models of thrombosis, including pulmonary embolism and myocardial infarction.

Polyphosphates are stored in the dense granules of platelets and when released, contribute to the procoagulant potential of the platelet. In regions of cellular death or severe inflammation, histones released from the tissue can bind to these polyphosphates, increasing the procoagulant activity more than 20-fold. Heparin analogues can block polyphosphate stimulation of coagulation by histones. In addition, neutrophils in hyperinflammatory environments can release their nuclear contents to form neutrophil extracellular traps (NETs). These NETs are effective in killing bacteria and other pathogens and also provide a potent agonist for the activation of platelets and the development of thrombi. Interestingly, heparin, an anticoagulant often used in the setting of inflammation, can disrupt the NETs and diminish the activation of platelets by histones and NETs.

Inhibition of Coagulation

There are three major natural anticoagulant mechanisms that serve to limit the coagulation process. These are tissue factor pathway inhibitor (TFPI), which blocks the initiation of coagulation by tissue factor-factor VIIa; the antithrombin-heparin mechanism, which inhibits thrombin and factors VIIa, Xa, and IXa; and the protein C pathway, which inactivates factors Va and VIIIa.

  1. Tissue factor pathway inhibitor (TFPI)
  2. Antithrombin-heparin mechanism
  3. Protein C pathway

Tissue Factor Pathway Inhibitor

TFPI is a complex molecule composed of three similar domains related to a protease inhibitor type known as Kunitz inhibitor. To inhibitor the tissue factor-factor VIIa complex, the Kunitz-1 domain of TFPI binds factor VIIa, whereas the Kunitz-2 domain binds factor Xa, either because the factor X is activated on tissue factor or (probably less effectively) by first reacting with factor Xa in solution and then inhibiting factor VIIa bound to tissue factor, thus blocking the initiation of coagulation. The carboxy terminal portion of TFPI is very basic, potentially facilitating interaction with the endothelium. Protein S can augment the activity of TFPI by increasing the rate of TFPI inactivation of factor Xa. The physiologic importance of TFPI is highlighted by the fact that gene deletion results in embryonic lethality apparently because of thrombosis and subsequent hemorrhage.

  1. Inhibiting Xa (Xa-TFPI complex)
  2. Xa-TFPI complex Inhibits FVIIa-TF complex
  3. TFPI is necessary for life

Antithrombin and Heparin

Antithrombin is the major inhibitor of the coagulation proteases thrombin, factor VIIa, factor Xa, and factor IXa. Antithrombin is a member of a large class of protease inhibitors referred to as serine protease inhibitors and abbreviated sermons. Antithrombin forms a very tight complex with these proteases. This reaction is rather slow with a half-life in the order of 30 seconds in plasma. Heparin markedly accelerates the reaction, thus accounting for most of its anticoagulant activity. There is a “bait” region in antithrombin that is involved in its interaction with the proteases. In the absence of heparin, this bait region is only partially available to the protease, resulting in the slow inhibition. Heparin binding to antithrombin induces a conformational change in antithrombin that enhances protease access to the bait loop.

In addition to the conformational change in antithrombin, heparin has additional roles in the inhibition of coagulation proteases. High-molecular-weight heparin can bind to both antithrombin and the protease, creating a situation where both reactants are brought into close proximity, thus increasing the reaction rate. This function is of variable importance with different proteases of the cascade. It is essential for thrombin inhibition, but plays a less important role in the inhibition of factor Xa. High-molecular-weight heparins accelerate factor Xa inhibition somewhat better than low-molecular-weight forms, but in contrast to most of the other heparin-mediated inhibitory functions, the additional acceleration gained by the high-molecular-weight forms is dependent on calcium ions. It is of interest that as heparins become processed to generate lower-molecular-weight fractions, such as enoxaparin, the capacity to promote thrombin inhibition versus factor Xa inhibition decreases. With the smallest functional form of heparin, the synthetic pentasaccharide fondaparinux, the ability to augment thrombin inhibition is almost completely lost, while good inhibition of factor Xa is maintained. Although heparin is a potent antithrombin-dependent anticoagulant, it is not effective against clot-bound thrombin or the factor Va-factor Xa complex assembled on membrane surfaces.

The importance of antithrombin is documented by the clinical observation that antithrombin deficiency, even to 50% of normal, is associated with significant thrombotic problems in humans and mice. Deletion of the gene in mice causes embryonic lethality, apparently in a mechanism that involves thrombosis followed by hemorrhage. Although heparin-like proteoglycans have been proposed to be important in modulating antithrombin function, immunohistochemical analysis indicates that most of these are localized to the basolateral side of the endothelium. No definitive deletion of heparin sulfate proteoglycans has been reported, possibly because there are alternative mechanisms for its biosynthesis. However, deletion of ryudocan, another heparin-like proteoglycan, is associated with a thrombotic phenotype.

  1. Antithrombin is ineffective against clot-bound thrombin or the factor Va-factor Xa complex assembled on membrane surfaces
  2. Heparin itself has no anticoagulation effect
  3. Heparin accelerates the anticoagulation capacity of antithrombin
  4. Deficiency of heparin-like proteoglycan potentiates patients at risk of thrombosis

The Thrombomodulin and Protein C Anticoagulation Pathway

The protein C pathway serves many roles, probably the primary role being to work to generate activated protein C (APC) that in turn inactivates factors Va and VIIIa to inhibit coagulation. The importance of this anticoagulant activity is readily apparent because patients born without protein C die in infancy of massive thrombotic complication (purport fulminans) unless provided a protein concentrate.

The protein C anticoagulant pathway serves to alter the function of thrombin, converting it from a procoagulant enzyme into the initiator of an anticoagulant response. This occurs when thrombin binds to thrombomodulin, a proteoglycan receptor primarily on the surface of the endothelium. Thrombomodulin binds thrombin with high affinity, depending on the posttranslational modifications of thrombomodulin. Binding thrombin to thrombomodulin blocks most of thrombin’s procoagulant activity such as the ability to clot fibrinogen, activate platelets, and activate factor V but does not prevent thrombin inhibition by antithrombin. The thrombin-thrombomodulin complex gains the ability to rapidly activate protein C. In the microcirculation, where there is high ratio of endothelial surface to blood volume, it has been estimated that the thrombomodulin concentration is in the range of 100 to 500 nM. Thus a single pass through the microcirculation effectively strips thrombin from the blood, initiates protein C activation, and holds a coagulantly inactive thrombin molecule in place for inhibition by antithrombin or protein C inhibitor. Activation of protein C is augmented approximately 20-fold in vivo by the endothelial cell protein C receptor (EPCR). EPCR binds both protein C and APC with similar affinity. The EPCR-APC complex is capable of cytoprotective functions, but at least with soluble EPCR, this complex is not an effective anticoagulant. Instead, when APC dissociates from EPCR, it can interact with protein S to inactivate factors Va and VIIIa and thus inhibit coagulation. Factor V increases the rate at which the APC-protein S complex inactivates factor VIIIa.

Thrombomodulin also increases the rate at which thrombin activates thrombin-activatable fibrinolysis inhibitor (TAFI) to a similar extent as it dose protein C. Once activated, TAFI releases C-terminal lysine and arginine residues of fibrin chains. C-terminal lysine residues on fibrin enhance fibrin degradation by serving as plasminogen- and tissue plasminogen activator-binding sites. Consequently, their removal by activated TAFI (TAFIa) attenuates clot lysis.

More than any other regulatory pathway except tissue factor, the protein C pathway is sensitive to regulation by inflammatory mediators. Tumor necrosis factor-alpha and IL-1beta downregulate thrombomodulin both in cell culture and in at least some patients with sepsis. Downregulation of thrombomodulin has been observed in animal models of diabetes, inflammatory bowel disease, reperfusion injury in the heart, over human atheroma, and in villitis, in addition to sepsis.

  1. Protein C, thrombomodulin, and EPCR are essential for life
  2. Protein C targets against factors Va and VIIIa
  3. EPCR increases the protein C activation by thrombin-thormbomodulin complex by about 20-fold
  4. Protein C’s anticoagulation function needs the help of protein S
  5. Thrombin-thrombomodulin complex removes the C-terminal lysine residues of fibrin, which attenuates clot fibrinolysis.

Regulation of Fibrinolysis

Fibrinolysis is the process by which fibrin clots are dissolved, either through natural mechanisms or with the aid of pharmaceutical interventions. Plasmin is the serine protease that solubilizes fibrin. Plasmin is generated by the activation of its precursor plasminogen either by natural activators, tissue plasminogen activator (tPA), the major activator in the circulation, or urokinase plasminogen activator (uPA), or by administration of recombinant tPA or streptokinase, a bacterial protein that promotes plasmin generation and aids in dissemination of the bacteria. Staphylokinase, a protein from Staphylococcus aureus, is similar to streptokinase and also has been examined as a potential therapeutic.

Fibrin plays an active role in its own degradation because it binds plasminogen and tPA, thereby concentrating them on the fibrin surface and promoting their interaction. The resultant plasmin cleaves fibrin and exposes C-terminal lysine residues that serve as additional plasminogen and tPA binding sites. TAFIa attenuates fibrinolysis by releasing these C-terminal lysine residues. Furthermore, lysine analogues, such as ε-aminocaproic acid or tranexamic acid, bind to tPA and plasminogen. Consequently, these lysine analogues can be used to treat patients with hyperfibrinolysis and can reduce bleeding complications.

Plasmin is not specific for fibrin and degrades a variety of other proteins. Consequently, plasmin is tightly controlled. There are two major inhibitors of fibrinolysis: α2-antiplasmin, and serpin that inactivates plasmin, and plasminogen activator inhibitor 1 (PAI-1), which inhibits tPA and uPA. α2-Antiplasmin is cross-linked to fibrin by activator factor XIII. PAI-1 is an intrinsically unstable serpin that can be stabilized by interaction with vitronectin. Because of its instability, the antigen and functional levels of PAI-1 are often quite different and can vary among individuals. PAI-1 is upregulated by lipopolysaccharide, tumor necrosis factor, and other inflammatory cytokines. PAI-1 levels are increased in vascular diseases such as atherosclerosis and in metabolic syndrome, sepsis, and obesity. Increased levels of PAI-1 result in decreased fibrinolytic activity, which increases the risk for thrombosis. PAI-1 is also stored in platelets and is released with platelet activation. Platelet-derived PAI-1 may limit the degradation of platelet-rich thrombi, such as those that trigger acute coronary syndromes.

Overall the fibrinolytic system is dynamic and responsive to local phenomena, such as platelet-derived PAI-1, as well as to systemic alterations like obesity and inflammation. In this sense, the fibrinolytic control mechanisms share many similarities with the control of coagulation, in which similar considerations affect their function.

Some Critical Notices Should Knowing When Using Warfarin

June 30, 2017 Anticoagulant Therapy, Hematology, Laboratory Medicine No comments , , , , , , , , , , , ,

PT/INR and Anticoagulation Status

For the vast majority of patients        , monitoring is done using the prothrombin time with international normalized ratio (PT/INR), which reflects the degree of anticoagulation due to depletion of vitamin K-dependent coagulation. However, attention must be paid that the PT/INR in a patient on warfarin may note reflect the total anticoagulation status of the patient in certain settings:

  • First few day of warfarin initiation

The initial prolongation of the PT/INR during the first one to three days of warfarin initiation does not reflect full anticoagulation, because only the factor with the shortest half-life is initially depleted; other functional vitamin K-dependent factors with longer half-lives (e.g., prothrombin) continues to circulate. The full anticoagulation effect of a VKA generally occurs within approximately one week after the initiation of therapy and results in equilibrium levels of functional factors II, IX, and X at approximately 10 to 35 percent of normal.

  • Liver disease

Individuals with liver disease frequently have abnormalities in routine laboratory tests of coagulation, including prolongation of the PT, INR, and aPTT, along with mild thrombocytopenia, elevated D-dimer, especially when liver synthetic function is more significantly impaired and portal pressures are increased. However, these tests are very poor at predicting the risk of bleeding in individuals with liver disease because they only reflect changes in procoagulant factors.

  • Baseline prolonged PT/INR

Some patients with the antiphospholipid antibody syndrome (APS) have marked fluctuations in the INR that make monitoring of the degree of anticoagulation difficult.

Time in the Therapeutic Range (TTR)

For patients who are stably anticoagulated with a VKA, the percentage of time in the therapeutic range (TTR) is often used as a measure of the quality of anticoagulation control. TTR can be calculated using a variety of methods. The TTR reported depends on the method of calculation as well as the INR range considered “therapeutic.” A TTR of 65 to 70 percent is considered to be a reasonable and achievable degree of INR control in most settings.

Factors Affecting the Dose-Response Relationship Between Warfarin and INR

  • Nutritional status, including vitamin K intake
  • Medication Adherence
  • Genetic variation
  • Drug interactions
  • Smoking and alcohol use
  • Renal, hepatic, and cardiac function
  • Hypermetabolic states

In addition, female sex, increased age, and previous INR instability or hemorrhage have been associated with a greater sensitivity to warfarin and/or an increased risk of bleeding.

Dietary Factors

Vitamin K intake – Individuals anti coagulated with warfarin generally are sensitive to fluctuations in vitamin K intake, and adequate INR control requires close attention to the amount of vitamin K ingested from dietary and other sources. The goal of monitoring vitamin K intake is to maintain a moderate, constant level of intake rather than to eliminate vitamin K from the diet. Specific guidance from anticoagulation clinics may vary, but a general principle is that maintaining a consistent level of vitamin K intake should not interfere with a nutritious diet. Patients taking warfarin may wish to be familiar with possible sources of vitamin K (in order to avoid inconsistency).

Of note, intestinal microflora produce vitamin K2, and one of the ways antibiotics contribute to variability in the prothrombin time/INR is by reducing intestinal vitamin K synthesis.

Cranberry juice and grapefruit juice have very low vitamin K content but have been reported to affect VKA anticoagulation in some studies, and some anticoagulation clinics advise patients to limit their intake to one or two servings (or less) per day.

Medication Adherence

Medication adherence for vitamin K antagonists can be challenging due to the need for frequent monitoring and dose adjustments, dietary restrictions, medication interactions, and, in some cases, use of different medication doses on different days to achieve the optimal weekly intake. Reducing the number of medications prescribed may be helpful, if this can be done safely.

Drug Interactions

A large number of drugs interact with vitamin K antagonists by a variety of mechanisms, and additional interacting drugs continue to be introduced. Determine clinically important drug interactions is challenging because the evidence substantiating claims for some drug is very limited; in other cases, the evidence is strong but the magnitude of effect is small. Patients should be advised to discuss any new medication or over-the-counter supplement with the clinician managing their anticoagulation, and clinicians are advised to confirm whether a clinically important drug-drug interaction has been reported when introducing a new medication in a patient anticoagulated with a VKA.

Smoking and Excess Alcohol

The effect of chronic cigarette smoking on warfarin metabolism was evaluated in a systematic review and that included 13 studies involving over 3000 patients. A meta-analysis of the studies that evaluated warfarin dose requirement found that smoking increased the dose requirement by 12 percent, corresponding to a requirement of 2.26 additional mg of warfarin per week. However, two studies that evaluated the effect of chronic smoking on INR control found equivalent control in smokers and non-smokers.

The mechanisms by which cigarette smoking interacts with warfarin metabolism is by causing enhanced drug clearance through induction of hepatic cytochrome P-450 activity by polycyclic aromatic hydrocarbons in cigarette smoke. Nicotine itself is not thought to alter warfarin metabolism.

The interaction between excess alcohol use and warfarin anticoagulation was evaluated in a case-control study that compared alcohol use in 265 individuals receiving warfarin who had major bleeding with 305 controls from the same cohort receiving warfarin who did not have major bleeding. The risk of major bleeding was increased with moderate to severe alcohol use and with heavy episodic drinking.

Mechanism by which alcohol use interacts with warfarin anticoagulation are many, and the contribution of various factors depends greatly on the amount of intake and the severity of associated liver disease. Excess alcohol consumption may interfere with warfarin metabolism. Severe liver disease may also be associated with coagulopathy, thrombocytopenia, and/or gastrointestinal varices, all of which increase bleeding risk independent of effects on warfarin metabolism.


The major comorbidities that affect anticoagulation control are hepatic disease, renal dysfunction, and heart failure. In addition, other comorbidities such as metastatic cancer, diabetes, or uncontrolled hyperthyroidism may also play a role.

The liver is the predominant site of warfarin metabolism. It is also the source of the majority of coagulation factors. Thus, liver disease can affect warfarin dosage, INR control, and coagulation in general. Importantly, individuals with severe liver disease are not “auto-anticoagulated,” because they often have a combination of abnormalities that both impair hemostasis and increase thrombotic risk.

Warfarin undergoes partial excretion in the kidney. Patients with kidney disease can receive warfarin, and management is generally similar to the population without renal impairment; however, dose requirement may be lower.

Heart failure has been shown to interfere with INR stabilization.

Acute illnesses may alter anticoagulation through effects on vitamin K intake, VKA metabolism, and medication interactions, especially infections and gastrointestinal illnesses.

Genetic Factors

Genetic polymorphisms have been implicated in altered sensitivity to warfarin and other vitamin K antagonists.

The Management of Disseminated Intravascular Coagulation (DIC)

June 10, 2013 Anticoagulant Therapy, Hematology, Pharmacotherapy, Physiology and Pathophysiology, Therapeutics No comments

Disseminated intravascular coagulation (DIC) is characterized by systemic activation of blood coagulation, which results in generation and deposition of fibrin, leading to microvascular thrombi in various organs and contributing to multiple organ dysfunction syndrome (MODS). Consumption and subsequent exhaustion of coagulation proteins and platelets may induce severe bleeding.

The International Society on Thrombosis and Haemostasis has suggested the following definition for DIC: An acquired syndrome characterized by the intravascular activation of coagulation with a simultaneously occurring thrombotic and bleeding problem, which obviously complicates the proper treatment.

DIC is not itself a specific illness; rather, it is a complication or an effect of the progression of other illnesses. It is always secondary to an underlying disorder and is associated with a number of clinical conditions such as sepsis and severe infection, trauma, organ destruction, malignancy, and so on.

DIC can be divided into acute DIC and chronic DIC. Acute DIC develops when sudden exposure of blood to procoagulants generates intravascular coagulation. Compensatory hemostatic mechanisms are quickly overwhelmed, and as a result, a severe consumptive coagulopathy leading to hemorrhage develops. In contrast, chronic DIC reflects a compensated state that develops when blood is continuously or intermittently exposed to small amounts of procoagulants. Compensatory hemostatic mechanisms are not overwhelmed, and there may be little obvious clinical or laboratory indication of the presence of DIC.


Four simultaneous mechanisms seem to result in the hematologic derangements seen in DIC. They are TF (tissue factor)-mediated thrombin generation, dysfunctional physiologic anticoagulant mechanisms, impaired fibrin removal due to depression of the fibrinolytic system, and inflammatory activation.

Thrombin generation and tissue factor

Exposure to TF in the circulation occurs via endothelial disruption, tissue damage, or inflammatory or tumor cell expression of procoagulant molecules (including TF). TF activates coagulation by forming TF-VIIa complex which activates thrombin (the complex cleaves fibrinogen to fibrin while simultaneously causing platelet aggregaton), which is the extrinsic pathway of coagulant cascades. After produced by TF/factor VIIa pathway, thrombin amplifies both clotting and inflammation.

While the extrinsic pathway plays an important role in thrombin generation in DIC, the intrinsic pathway may also be activated in DIC, but it appears not to play an important role. The actual source of the TF has not been established with certainty. TF may be expressed on mononuclear cells in vitro, on polymorphonuclear leukocytes, on circulating monocytes of patients with severe infection, and on injured endothelial cells. Whereas, the  importance of the role TF expresson on injured endothelial play remains to be determined.

Impaired coagulation inhibitor systems

Thrombin generation is usually tightly regulated by multiple hemostatic mechanisms. However, once intravascular coagulation commences, compensatory mechanisms are overwhelmed or incapacitated. Impaired functioning of various natural regulating pathways of coagulation activation may amplify further thrombin generation and contribute to fibrin formation.

Three main substances consist the coagulation inhibitor systems including antithrombin, protein C, and TF pathway inhibitor (TFPI).

Usually patients with DIC have markedly reduced antithrombin level. The causation may be that antithrombin is continuously consumed by ongoing activation of coagulation, elastase produced by activated neutrophils degrades antithrombin, further antithrombin is lost to capillary leakage during DIC, and that production of antithrombin is impaired secondary to liver damage resulting from underperfusion and microvascular coagulation.

Protein C along with protein S, severs as a major anticoagulant compensatory mechanism. Under normal conditions, protein C is activated by thrombin when complexed on the endothelial cell surface with thrombomodulin. Activated protein C combats coagulation by proteolytic cleavage of factors Va and VIIIa and proteolyzes RAR1 when bound to the endothelial cell protein C receptor (EPCR). Impaired functioning of the protein C pathway is mainly due to down-regulation of thrombomodulin expression or its inactivation by cellular reactive oxygen species on endothelial cells by proinflammatory cytokines. Also the level of protein C is reduced during DIC as a result of continuously consumption, lost to capillary leakage and so on (similar to those described for antithrombin). So both low level and diminished activation of protein C result in the impaired anticoagulation function of coagulation inhibitor systems.

TF pathway inhibitor (TFPI) is another anticoagulant rechanism that is disabled in DIC. TFPI reversibly inhibits factor Xa and thrombin (indirectly) and has the ability to inhibit the TF-VIIa complex. During the DIC TFPI is relative insufficient which reduces the function of the coagulation inhibitor systems.

Defective fibrinolysis

The intravascular fibrin produced by thrombin is normally eliminated by a process termed fibrinolysis. Experimental models indicate that at the time of maximal activation of coagulation, the fibrinolytic system is largely shut off. Experimental bacteremia and endotoxemia result in a rapid increase in fibrinolytic activity, most probably caused by release of plasminogen activators from endothelial cells. However, this profibrinolytic response is almost immediately followed by suppression of fibrinolytic activity due to a sustained increase in plasma levels of PAI-1.

However, rare cases of DIC are characterized by a severe hyperfibrinolytic state on top of an activated coagulation system. Examples of such situations are the DIC that occurs as a complication of acute promyelocytic leukemia (APL/AML-M3) and some forms of adenocarcinoma. Clinically, these patients suffer from severe bleeding.

Inflammatory activation

Inflammatory and coagulation pathways interact in substantial ways. It is clear that there is cross-communication between the 2 systems, whereby inflammation gives rise to activation of the clotting cascade and the resultant coagulation stimulates more vigorous inflammatory activity. For example, thrombin produced by TF/factor VII pathway can amplify inflammation.

Screen Shot 2014-10-26 at 10.30.24 PMEtiology

Several disease states may lead to the development of DIC, generally via 1 of the following 2 pathways: 1. A systemic inflammatory response, leading to activation of the cytokine network and subsequent activation of coagulation (e.g., in sepsis or major trauma);2. Release or exposure of procoagulant material into the bloodstream (e.g., in cancer, crush brain injury, or in obstetric cases). These disease states include infections, maligancies, obstetric cases, transfusion related cases such as hemolytic reactions, trauma, and others.

Bacterial infection (in particular, bloodstream infection) is commonly associated with DIC. There is no difference in the incidence of DIC between patients with gram-negative and those with gram-positive sepsis. Systemic infections with other microorganisms, such as viruses and parasites, may lead to DIC as well. Factors involved in the development of DIC in patients with infections may be specific cell membrane components of the microorganism or bacterial exotoxins. These component cause a generalized inflammatory response, characterized by the systemic occurrence of proinflammatory of cytokines.

Table 1. Causes of Acute (Hemorrhagic) Disseminated Intravascular Coagulation

InfectiousBacterial (eg, gram-negative sepsis, gram-positive infections, rickettsial) Viral (eg, HIV, cytomegalovirus [CMV], varicella-zoster virus [VZV], and hepatitis virus) Fungal (eg, Histoplasma)Parasitic (eg, malaria)
MalignancyHematologic (eg, acute myelocytic leukemia) Metastatic (eg, mucin-secreting adenocarcinoma)
ObstetricPlacental abruptionAmniotic fluid embolism Acute fatty liver of pregnancyEclampsia
TraumaBurns Motor vehicle accidents Snake envenomation
TransfusionHemolytic reactions Transfusion
OtherLiver disease/acute hepatic failure* Prosthetic devices Shunts (Denver or LeVeen)Ventricular assist devices
*Some do not classify this as DIC; rather, it is liver disease with reduced blood coagulation factor synthesis and reduced clearance of activate products of coagulation.


DIC may occur in 30-50% of patients with sepsis, and it develops in an estimated 1% of all hospitalized patients. The prognosis of DIC depends on the severity of the coagulopathy and on the underlying condition that led to DIC. However, assigning numerical figures to DIC-specific morbidity and mortality is difficult. In general, if the underlying condition is self-limited or can be appropriately handled, DIC will disappear, and the coagulation status will normalize. A patient with acute hemorrhagic DIC that is associated with metastatic gastric carcinoma likely has a lethal condition that does not alter patient demise, regardless of treatment. On the other hand, a patient with acute DIC associated with abruptio placentae needs quick recognition and obstetric treatment; the DIC will resolve with the treatment of the obstetric catastrophe.


Diagnosis of DIC can be difficult, especially in cases of chronic. Here we focus on acute DIC because it much worsen than chronic DIC with higher morbidity and mortality. The diagnosis of DIC relies on multiple clinical and laboratory determinations. The International Society on Thrombosis and Haemostasis (ISTH) developed a scoring system for the diagnosis of overt DIC that makes use of laboratory tests available in almost all hospital laboratories. The presence of an underlying disorder known to be associated with DIC (see Etiology) is a sine qua non for the use of this diagnostic algorithm. A score of 5 or higher indicates overt DIC, whereas a score of less than 5 does not rule out DIC but may indicate DIC that is not overt. Prospective validation studies show this scoring system to be highly accurate for the diagnosis of DIC. The sensitivity of the DIC score for a diagnosis of DIC is 91-93%, and the specificity is 97-98%.

Figure 1. Diagnostic Algorithm for The Diagnosis of Overt Disseminated Intravascular Coagulation

In clinical practice, a diagnosis of DIC can often be made by a combination of platelet count, measurement of global clotting times (aPTT and PT) and 1 or 2 clotting factors and inhibitors, and testing for FDPs.

Platelet count: typically, moderate-to-severe thrombocytopenia is present in DIC. Thrombocytopenia is seen in as many as 98% of DIC patients, and the platelet count can dip below 50 × 109/L in 50%. A decreasing treand in platelet counts or a grossly reduced absolute platelet count is a sensitive (though not specific) indicator of DIC. Repeated platelet counts are often necessary, a single platelet measurement may indicate a level within the normal range, whereas trend values might show a precipitous drop from previous levels.

Global clotting times: both aPTT and PT are typically prolonged. In as many as 50% of DIC patients, however, a normal or even an attenuated PT and aPTT may be encountered; consequently, such values cannot be used to exclude DIC. This phenomenon may be attributed to certain activated clotting factors present in the circulation, such as thrombin or Xa, which may in fact enhance thrombin formation.

It should be emphasized that serial coagulation tests are usually more helpful than single laboraatory results in establishing the diagnosis of DIC. It is also important to note that the PT, not the INR should be used in the DIC monitoring process. INR is recommended only for monitoring oral anticoagulant therapy.

DIC is associated with an unusual light transmission profile on the aPTT, known as a biphasic waveform. In one study, the degree of biphasic waveform abnormality had an increasing positive predictive value for DIC, independent of clotting time prolongation. In addition, the waveform abnormalities are often evident before more conventionally used laboratory value derangements, making this a quick and robust test for DIC.

Clotting factors: the prolongation of global clotting times may reflect the consumption and depletion of various coagulation factors, which may be further substantiated by the measurement of selected coagulation factors, such as factor V and factor VII.

Clotting inhibitors: protein C and antihrombin are 2 natural anticoagulants that are frequently decreased in DIC. There is some evidence to suggest that they may serve roles as prognostic indicators. Nonetheless, the practical application of measuring these anticoagulants may be limited for most practitioners the test may not generally available.

Fibrin: because fibrin is a central component of DIC, it would seem logical to assume that if soluble fibrin is elevated, the diagnosis of DIC can be made with confidence. However, soluble fibrin levels are not available to most clinicians within a relevant time fram.

Fibrinogen: the massive fibrin deposition in DIC suggests that fibrinogen levels would be decreased. Accordingly, measurement of fibrinogen has been widely advocated as a useful tool for the diagnosis of DIC; however, it is not, in fact, very helpful. Fibrinogen, as a positive acute-phase reactant, is increased in inflammation, and whereas values may decrease as the illness progresses, they are rarely low. On study demonstrated that in up to 57% of DIC patients, the levels of fibrinogen may in fact remain within normal limit.

Fibrin degradation products (FDPs): fibrinolysis is an important component of DIC; thus, there will be evidence of fibrin breakdown, such as elevated levels D-dimer and FDPs. D-dimer elevation means that thrombin has proteolyzed fibrinogen to form fibrin that has been cross-linked by thrombin-activated factor XIIIa. When fibrin becomes cross-linked insoluble, a unique D-D domain neoepitope forms. This cross-linked insoluble fibrin is then proteolyzed uniquely by plasmin to liberate the soluble D-D dimer. Thus, the D-dimer measures prior thrombin and plasmin formation. On the other hand, FDPs only inform that  plasmin has been formed and it cleaved soluble fibrinogen, fibrin, or insoluble cross-linked fibrin. D-dimer is the better test for DIC. However, FDPs are not used as often.

Thrombomodulin: This is the specialized test for DIC. Evidence suggests that serum levels of thrombomodulin, a marker for endothelial cell damage, correlate well with the clinical course of DIC, the development of multiple organ dysfunction syndrome (MODS), and mortality in septic patients. Thrombomodulin is elevated in DIC, and such elevation and not only correlates well with the severity of DIC but also can serve as a maker of early identification and monitoring of DIC.

Therapeutic Approach of Disseminated Intravascular Coagulation (DIC)

Treatment of DIC is controversial. Generally, the therapeutic approach consists of management of underlying disease, administration of blood components and coagulation factors, and restoration of anticoagulant pathways.

A DIC scoring system developed by Bick has been used to assess the severity of the coagulopathy as well as the effectiveness of therapeutic modalities.[1] The scoring sytem is below (Table 2).

Table 2 Dic Scoring System by Bick

fibrinopeptide A in ng/mL< 30
3 – 101
11 – 402
41- 703
> 704
profragment 1,2 in nM0.2 – 2.70
2.8 – 5.91
6.0 – 7.42
7.5 – 10.03
> 10.04
D-dimer µg/L< 5000
500 – 1,0001
1,001 – 2,0002
2,001 – 2,9993
>= 3,0004
FDP (fibrin degradation products) in µg/mL< 100
10 – 401
41 – 802
81 –1203
> 1204
antithrombin (% of normal)85 – 125%0
75 – 84%1
65 – 74%2
54 – 64%3
< 54%4
alpha-2-antiplasmin (% of normal)75 – 120%0
65 – 74%1
55 – 64%2
45 – 54%3
< 45%4
fibrinogen in mg/dL150 – 3500
100 – 1491
75 – 992
50 – 743
< 504
platelet count per µL150,000 – 450,0000
100,000- 149,9991
75.000 – 99,9992
50,000 – 74,9993
< 50,0004
temperature in °C<= 29.94
30 – 31.93
32 – 33.92
34 – 35.91
36 – 38.40
38.5 – 38.91
39 – 40.93
>= 414
mean arterial pressure in mm Hg<= 494
50 – 692
70 – 1090
110 – 1292
130 – 1593
>= 1604
pulse rate in beats/minute<= 394
40 – 543
55 – 692
70 – 1090
110 – 1392
140 – 1793
>= 1804
Parameter (cont.)FindingPoints
respiratory rate per minute<= 54
6 – 92
10 – 111
12 – 240
25 – 341
35 – 493
>= 504
PaO2 in mm Hg80 – 1000
70 – 791
60 – 692
55 – 603
< 554
pH< 7.154
7.15 – 7.243
7.25 – 7.322
7.33 – 7.490
7.50 – 7.591
7.60 – 7.693
>= 7.704
creatinine in mg/dL< 0.62
0.6 – 1.40
1.5 – 1.92
2.0 – 3.43
>= 3.54
LDH in U/L<= 1930
194 – 2251
226 – 2502
251 – 2753
> 2754
albumin in g/dL3.5 – 5.50
3.0 – 3.41
2.6 – 2.92
2.1 – 2.53
<= 2.04
sodium in mEq/L<= 1104
111 – 1193
120 – 1292
130 – 1490
150 – 1541
155 – 1592
160 – 1793
>= 1804
potassium in mEq/L< 2.54
2.5 – 2.92
3.0 – 3.41
3.5 – 5.40
5.5 – 5.91
6.0 – 6.93
>= 7.04
hematocrit, in percent< 204
20 – 29.92
30 – 45.90
46 – 49.91
50 – 59.92
>= 604
total WBC count per µL< 1,0004
1,000 – 2,9992
3,000 – 14,9990
15,000 – 19,9991
20,000 – 39,9992
>= 40,0004


• 0 points is assigned to normal findings

• mean arterial pressure = [(systolic pressure) + (2 × (diastolic pressure))] / 3

• Since LDH shows some variability between laboratories, the LDH range can be rewritten: 0 points (<= 100% upper limit of normal); 1 point (> 100% ULN – 117% ULN); 2 points (> 117% ULN – 130% ULN); 3 points (>130% ULN – 142% ULN); 4 points (> 142% ULN)

DIC score = 100 – SUM(points for all parameters)

DIC scoreInterpretation
>= 90DIC unlikely
75 – 89mild DIC
50 – 74moderate DIC
< 49severe DIC


• maximum DIC score: 100

• minimum DIC score: 16


Underlying Disease

The management of DIC should primarily be directed at treatment of the underlying disorder. Often DIC component will resolve on its own with treatment. A DIC scoring system has been proposed by Bick to assess the severity of the coagulopathy as well as the effectiveness of therapeutic modalities (Table 2).

Blood Components and Coagulation Factors

Typically, DIC results in significant reductions in platelet count and increases in coagulation times. However, platelet and coagulation factor replacement should not be instituted on the basis of laboratory results alone; such therapy is indicated only in patients with active bleeding and in those requiring an invasive procedure or who are otherwise at risk for bleeding complications.

Platelet transfusion may be considered in patients with DIC and severe thrombocytopenia, in particular, in patients with bleeding or in patients at risk for bleeding. The threshold for transfusion platelets varies. Most clinicians provide platelet replacement in nonbleeding patients if platelet counts drop below 20 × 109/L, though the exact levels at which platelets should be transfused is a clinical decision based on each patient’s clinical condition. In some instances, platelet transfusion is necessary at higher platelet counts, particularly if indicated by clinical and laboratory findings. In actively bleeding patients, platelet levels from 20 × 109/L to 50 × 109/L are grounds for platelet transfusion.

Previously, concerns have been expressed regarding the possibility that coagulation factor replacement therapy might “add fuel to the fire” of consumption; however, this has never been established in research studies.

It is generally considered that cryoprecipitate and coagulation factor concentrates should not routinely be used as replacement therapy in DIC, because they lack several specific factors (e.g., factor V). Additionally, worsening of the coagulopathy via the presence of small amounts of activated factors is a theoretical risk.

Specific deficiencies in coagulation factors, such as fibrinogen, can be corrected by administration of cryoprecipitate or purified fibrinogen concentrate in conjunction with fresh frozen plasma (FFP) administration.


Experimental studies have suggested that heparin can at least partly inhibit the activation of coagulation in cases of sepsis and other causes of DIC. However, a beneficial effect of heparin on clinically important outcome events in patients with DIC has not yet been demonstrated in controlled clinical trials. Moreover, antithrombin, the primary target of heparin activity, is markedly decreased in DIC, which means that the effectiveness of heparin therapy will be limited without concomitant replacement of antithrombin.

Furthermore, there are well-founded concerns with respect to anticoagulating DIC patients who are already at high risk for hemorrhagic complications. It is generally agreed that therapeutic doses of heparin are indicated in cases of obvious thromboembolic disease or where fibrin deposition predominates.

Restoration of Anticoagulant Pathways

The antithrombin pathway is largely depleted and incapacitated in acute DIC. As a result, several studies have evaluated the utility of antithrombin replacement in DIC. Most have demonstrated benefit in terms of improving laboratory values and even organ function. However, large-scale randomized trials have failed to demonstrate any mortality benefit in patients treated with antithrombin concentrate.

Activated protein C (APC) is an important regulator of coagulation. In studies of patients with sepsis who had associated organ failure, APC has been shown to reduce mortality and improve organ function. Protein C concentrate has been used to treat coagulation abnormalities in adult patients with sepsis. A study found protein C concentrate to be safe and useful in restoring coagulation and hematologic parameters; however further study is required.

Tissue factor pathway inhibitor (TFPI) has been shown very promising to arrest DIC and to prevent the mortality and end-organ damage in animal studies. However, a large phase III trial of TFPI in human with DIC did not show any mortality benefit. Recombinant thrombomodulin (rTM) can be used for treatment of DIC in cases of severe sepsis and hematopoietic malignancy. rTM not only allows the conversion of protein C to APC, but also inhibits the inflammatory process by interacting with high-mobility group B (HBGM-1). rTM has shown beneficial effects on DIC parameters and clinical outcome in initial trials, which it was found to yield significantly improved control of DIC in comparison with unfractionated heparin, particularly with respect to the control of persistent bleeding diathesis.


1. Rodger L. Bick. Disseminated Intravascular Coagulation: Objective Clinical and Laboratory Diagnosis, Treatment, and Assessment of Therapeutic Response. Semin Thromb Hemost 1996; 22(1): 69-88.

Nine agents in one Rx. and twenty drug interactions found (Not finished)

July 20, 2012 Anticoagulant Therapy, Cardiology, Drug Interactions 2 comments , , , ,

This afternoon I met a perscription that consist of nine different agents, which have twenty drug interactions. Many of them are cardiovascular drugs. They are  Beta-Blockers, Electrolytes, Statins, ARBs, Inotropic Agents, Thiazide, Calcium Channel Blockers, and Benzodiazepines. I list them and their dosage below.

  1. Alprazolam 0.4 mg po Qd
  2. Metoprolol 12.5 mg po Bid
  3. Potassium Chloride 1 g po Bid
  4. Simvastatin 20 mg po Qn
  5. Irbesartan 0.15 g po Qd
  6. Irbesartan/Hydrochlorothiazide 1 tablet po Qd
  7. Digoxin 0.125 mg po Qd
  8. Amlodipine 5 mg po Qd
  9. Warfarin 2.5 mg po Qd

I check these nine drug in Multi-Dug Interaction Chechker and find there are twenty drug interactions between these nine drugs. They are:

Serious – Use alternative

Amlodipine + Simvastatin. Amlodipine increases levels of simvastatin by Other (See comment). Possible serious or life-threatening interaction. Monitor closely. Use alternatives if available. Comment: Benefits of combination therapy should be carefully weighed against the  potential risks of combination. Potential for increased risk of myopathy/rhabdomyolysis. Limit simvastatin dose to no more than 20 mg/day when used concurrently.

Significant – Monitor Closely

Hydrochlorothiazide + Digoxin. Hydrochlorothiazide increases effects of digoxin by pharmacodynamic synergism. Significant interaction possible, monitor closely. Hypokalemia increases digoxin effects.

Potassium Chloride + Hydrochlorothiazide. Potassium chloride increases and hydrochlorothiazide decreases serum potassium. Effect of interaction is not clear, use caution. Potential for dangerous interaction. Use with caution and monitor closely.

Simvastatin + Warfarin. Simvastatin, warfarin. Either increases effects of the other by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Significant – Monitor Closely. Competition by each drug for CYP3A4-mediated metabolism may result in increased INR and increased risk of rhabdomyolysis.

Simvastatin + Digoxin. Simvastatin will increase the level or effect of digoxin by P-glycoprotein (MDR1) efflux transporter. Significant – Monitor Closely.

Digoxin + Hydrochlorothiazide. Digoxin will increase the level or effect of hydrochlorothiazide by basic (cationic) drug competition for renal tubular clearance. Significant – Monitor Closely.

Metoprolol + Irbesartan. Metoprolol, irbesartan. Mechanism: pharmacodynamic synergism. Significant – Monitor Closely. Risk of fetal compromise if given during pregnancy.

Alprazolam + Digoxin. Alprazolam increases levels of digoxin by unknown mechanism. Significant – Monitor Closely.

Metoprolol + Digoxin. Metoprolol increases effects of digoxin by pharmacodynamic synergism. Significant – Monitor Closely. Enhanced bradycardia.

Metoprolol + Amlodipine. Metoprolol and amlodipine both increase anti-hypertensive channel blocking. Significant – Monitor Closely.

Irbesartan + Potassium Chloride. Irbesartan and potassium chloride both increase serum potassium. Significant – Monitor Closely.

Metoprolol + Potassium Chloride. Metoprolol and potassium chloride both increase serum potassium. Significant – Monitor Closely.

Potassium Chloride + Digoxin. Potassium chloride and digoxin both increase serum potassium. Significant – Monitor Closely.

Irbesartan + Metoprolol. Irbesartan and metoprolol both increase serum potassium. Significant – Monitor Closely.

Irbesartan + Digoxin. Irbesartan and digoxin both increase serum potassium. Significant – Monitor Closely.

Irbesartan + Hydrochlorothiazide. Irbesartan increases and hydrochlorothiazide decreases serum potassium. Effect of interaction is not clear, use caution. Significant – Monitor Closely.

Metoprolol + Digoxin. Metoprolol and digoxin both increase serum potassium. Significant – Monitor Closely.

Metoprolol + Hydrochlorothiazide. Metoprolol increases and hydrochlorothiazide decreases serum potassium. Effect of interaction is not clear, use caution. Significant – Monitor Closely.

Digoxin + Hydrochlorothiazide. Digoxin increases and hydrochlorothiazide decreases serum potassium. Effect of interaction is not clear, use caution. Significant – Monitor Closely.

Irbesartan + Irbesartan/Hydrochlorothiazide (Not listed in the multi-drug interaction checker. I add this interaction by myself). Both Irbesartan and Irbesartan/Hydrochlorothiazide increase the level or effects of each other. The combination use of these two drugs is repeated administration and may enhance adverse effects of Irbesartan. I think this combination use should be avoid absolutely.

I alysis these twenty drug interactions. These twenty drug interactions include ten refered to  potassium disorder, three refered to pharmacodynamic synergism, one refered to myopathy/rhabdomyolysis, one hepatic/instestinal enzyme, one MDR1 (P-gp), one renal tubular excretion, one unknown, one anti-hypertension channel, and one repeated administration.

I think the next thing to do is to modify this pharmacotherapy regimen as there are many drug interactions in this regimen.

Food and drug interactions with emerging oral anticoagulants

May 15, 2012 Anticoagulant Therapy, Drug Interactions, Therapeutics No comments , ,

Food Interactions With Anticoagulant Drugs.

By Michael O’Riordan

June 8, 2010 (Maywood, Illinois) — A new review warns physicians to be aware of the potential for drug and dietary interactions with the emerging oral anticoagulants [1]. At present, there are few documented interactions with the new drugs, including dabigatran (Pradaxa, Boehringer Ingelheim), rivaroxaban (Xarelto, Johnson & Johnson), and apixaban (Bristol-Myers Squibb/Pfizer), but considering the extensive food and drug interactions with warfarin, caution should be taken with the new agents, according to researchers.

“Many unknowns remain as to how the new oral anticoagulants will behave in the real-world patient population,” write authors Drs Jeanine Walenga and Cafer Adiguzel (Loyola University Medical Center, Maywood, IL) in the June 2010 issue of the International Journal of Clinical Practice. “As evaluations of the new oral anticoagulants continue, the issue of drug interactions needs to be properly evaluated, particularly as some of the interacting drugs are used to treat potentially life-threatening conditions.”

One recent study reported by heartwire showed that the safety of warfarin, a vitamin-K antagonist, can be compromised by many popular herbal and nonherbal supplements. In fact, eight of the 10 most widely used supplements interact with warfarin, and many of these are associated with significant changes in the international normalized ratio (INR). Cranberry, garlic, ginkgo, and saw palmetto have been linked to increased rates of bleeding, whereas others have been shown to cause changes in prothrombin times, which would result in a need to alter warfarin doses.

Little Known About Food, But Caution Still Needed

In their review, Walenga and Adiguzel note that the new and emerging oral anticoagulants have a “rapid onset of action and a predictable anticoagulant effect,” but little is known about potential interactions with food. They point out the various physiological parameters can alter the pharmacokinetics of orally administered drugs, such as changes in gastric pH balance and intestinal motility and binding, and these can be affected by eating and taking the drugs at the same time.

Regarding drug interactions, dabigatran is contraindicated with quinidine, a drug used to treat cardiac arrhythmias and malaria. Caution should also be used when dabigatran is prescribed in combination with inhibitors or inducers of P-glycoprotein (P-GP), such as amiodarone, clarithromycin, and rifampin. Rivaroxaban, as well as possibly apixaban, is contraindicated with drugs that inhibit both cytochrome P450 3A4 (CYP3A4) and P-GP pathways, such as azole antimycotics, ritonavir, and clarithromycin, among others. Caution should be exercised prescribing rivaroxaban with a drug that inhibits either the CYP3A4 only or P-GP pathway only.

One over-the-counter supplement that the reviewers highlight as a possible problem with the new oral anticoagulants is St John’s wort, a herb taken frequently for depression. St John’s wort is known to reduce the anticoagulant effect of warfarin.

There is also risk of bleeding when using the new oral anticoagulants in combination with an antiplatelet agent, such as clopidogrel, or nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin.

“In addition to drug and food interactions, it is equally important to consider liver, kidney, and other common disease states that the US population experiences, particularly if these patients have been excluded from clinical trials,” write Walenga and Adiguzel. Although dabigatran and rivaroxaban are contraindicated in patients with severe liver impairment, they might inadvertently be given to patients in whom clinical symptoms are not pronounced, a population that has not been extensively studied.

The reviewers recommend clinicians use caution with the new drugs in older patients, particularly since this population often has long-term comorbid conditions.