Nonplatelet Hemostatic Disorders

Updated: May 12, 2016
  • Author: Muhammad A Mir, MD, FACP; Chief Editor: Perumal Thiagarajan, MD  more...
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Overview

Overview

Blood coagulation is triggered by the exposure of tissue factor at injury sites, leading to the generation of minute quantities of thrombin. Thrombin, in turn, activates platelets, as well as factors XI, VIII, and V, and triggers the sequential activation of factors XI, IX, X, and prothrombin on the activated platelet surface, leading to the generation of sufficient thrombin to convert fibrinogen to fibrin and affect hemostasis. Platelets localize coagulation to the hemostatic thrombus and protect coagulation enzymes from inhibition by plasma and platelet inhibitors, thus preventing disseminated intravascular coagulation (DIC).

Abnormalities in the coagulation cascade that are independent of the platelet protective mechanisms can affect hemostasis. These abnormalities may be inherited or acquired.

Disorders of nonplatelet hemostasis can be divided into 2 groups based on whether they increase or decrease coagulation. The former may lead to thrombosis, the latter to hemorrhage. Such a division is not absolute, since some disorders may have both hemorrhagic and thrombotic manifestations.

Coagulation-promoting conditions include the following:

Coagulation-impeding conditions include the following:

Hemostatic disorders may also be separated according to origin, ie, inherited or acquired.

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Fibrinogen Disorders

Fibrinogen disorders can be quantitative (afibrinogenemia) or qualitative (dysfibrinogenemia), and they may be congenital or acquired. Afibrinogenemia is defined as a deficiency or absence of fibrinogen (coagulation factor I) in the blood. Dysfibrinogenemias involve structural defects in fibrinogen that alter the conversion of fibrinogen to fibrin.

Approximately 300 abnormal fibrinogens have been reported, and about 83 structural defects have been identified. [1] The most common structural defect involves the fibrinopeptides and their cleavage sites; the second most common involves the gamma-chain polymerization region.

  • Mechanisms of dysfibrinogenemias include the following:
  • Impaired release of fibrinopeptides
  • Defective fibrin polymerization
  • Abnormal cross-linking by activated factor XIIIa (factor XIIIa)
  • Abnormal interactions with platelets
  • Defective fibrinolysis
  • Defective assembly of the fibrinolytic system
  • Abnormal calcium binding

Some patients with dysfibrinogenemia have additional hemostasis defects, including deficiencies in antithrombin, protein C, protein S, and factor V Leiden. [2]

The true prevalence of congenital fibrinogen disorders is unknown. The condition appears to be rare, however, with only 400 families reported as of 2012. [3, 4] Of these patients, 55% were asymptomatic (their cases detected by chance), 25% had bleeding symptoms, and 20% presented with thrombosis. The prevalence of dysfibrinogenemia in patients with a history of venous thrombosis is low (0.8%), as deduced from 9 studies in 7 countries on 2376 subjects. [4] No variation by race, age, or sex is known. Mortality is related to the severity of bleeding and/or to thrombotic complications at presentation.

Presentation

While most patients with dysfibrinogenemia are clinically asymptomatic, some present with a bleeding diathesis, others with thrombophilia, and others with both bleeding and thromboembolism. [2]

Approximately half of the mutations are clinically silent. Hemorrhage and thrombosis occur in almost equal numbers of cases. Severe bleeding is rare and is typically limited to postpartum bleeding, although isolated cases of patients with intraabdominal hemorrhage presenting with acute abdomen have been reported. [5, 6, 7] Dysfibrinogenemias present particular problems for the obstetrician because women affected by these disorders are at increased risk of first-trimester bleeding, spontaneous abortion, and/or postpartum thrombosis. [8]

The diagnosis of afibrinogenemia/dysfibrinogenemia should be considered in a patient who has bleeding or thrombosis unexplained by other common causes. A high level of clinical suspicion should be maintained in patients with other inherited disorders of hemostasis, such as protein C or S deficiency.

Diagnosis

The laboratory diagnosis of dysfibrinogenemias is difficult. Fibrinogen antigen level is preserved but there is a marked decrease in activity. [9] . Prothrombin time (PT) appears to be more sensitive than activated partial thromboplastin time (aPTT). Thrombin time (TT) and reptilase time (RT) are typically prolonged. [10] Fibrinogen levels are usually less than 100 mg/dL in the absence of iatrogenic causes (eg, massive blood loss, antifibrinolytics agents). Screening test results (eg, PT, aPTT) may be within reference ranges or only slightly prolonged. [11] Fibrinogen levels are decreased with DIC, primary and secondary fibrinolysis, and liver disease.

Because fibrinogen is an acute-phase protein reactant, increased levels may be observed with inflammation. Pregnancy and oral contraceptive use may also increase plasma fibrinogen levels. Plasma fibrinogen levels vary between the sexes and with weight, glucose levels, triglyceride values, and low levels of high-density lipoprotein cholesterol in healthy adults. [12]

Because of all these variations, many clinicians consider measurement of fibrinogen activity by thromboelastography to be the most accurate measurement of dysfibrinogenemia or qualitative dysfunctions. [13, 14]

Treatment

Treatment of afibrinogenemia/dysfibrinogenemia depends on the presenting clinical setting. Plasma fibrinogen is best replaced by cryoprecipitate. Purified, virally inactivated fibrinogen concentrates (eg, RiaSTAP) can be used if available. [15, 16]

Prophylactic blood product or fibrinogen therapy has no role. Recommendations for a desired plasma fibrinogen level for specific conditions are difficult to find because most physicians rely on correction of the clinical hemostatic abnormality as an endpoint. Kobayashi et al recommend that the fibrinogen level must be at least 0.60 g/L and, if possible, more than 1 g/L during pregnancy in patients with congenital afibrinogenemia. They maintain a plasma level of 150-200 g/dL during labor to prevent placental abruption.

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Vascular and Nonvascular Hemostatic Disorders

The following disorders have been classified as nonplatelet vascular and nonvascular hemostatic disorders, although they rarely manifest as significant bleeding or thrombotic problems [17] :

Abnormal circulating protein-related disorders

Abnormal circulating proteins may precipitate in the microvasculature, leading to localized thrombosis. These thromboses may be monoclonal, such as those produced in multiple myeloma and Waldenstrom macroglobulinemia, or they may be polyclonal, such as those found in the cryoglobulinemias. [18] Abnormal circulating proteins are associated with infectious, autoimmune, and neoplastic disorders. Patients typically present with purpuric skin rash, urticaria, arthralgia, motor-sensory polyneuropathy, and diffuse proliferative glomerulonephritis. Laboratory findings may indicate anemia, rheumatoid factor, and decreased complement levels, as well as abnormal populations of paraproteins and/or immunoglobulins. [19, 20]

Purpuras

Purpuras form another group of vascular hemostatic disorders. Hyperglobulinemic purpura caused by increased gamma-globulin levels is similar in presentation to those of the disorders described above. [21]

Henoch-Schönlein purpura (HSP) is a form of nonthrombocytopenic purpura due to hypersensitivity vasculitis and is primarily observed in children. [22, 23] The condition is usually benign, and it manifests in a variety of clinical symptoms, including urticaria and erythema, arthropathy and arthritis, gastrointestinal problems, and renal involvement. Two cases of acute appendicitis have been reported. [24] On rare occasions, patients have life-threatening hemorrhage that requires blood and blood-product support. [25] Recently, soluble urine transferrin receptor has been proposed a potential marker for HSP nephritis. [26]

Waterhouse-Friderichsen syndrome

Waterhouse-Friderichsen syndrome is a condition characterized by the abrupt onset of fever, petechiae, arthralgia, weakness, and myalgias, followed by acute hemorrhagic necrosis of the adrenal glands and severe cardiovascular dysfunction. The syndrome is most often associated with meningococcal septicemia but may occur as a complication of sepsis caused by other organisms, including certain streptococcal species. This disorder may be associated with a history of splenectomy. [27]

Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome is a rare X-linked immunodeficiency syndrome characterized by eczema, thrombocytopenic purpura, and recurrent pyogenic infection. The syndrome is observed exclusively in young boys. Typically, immunoglobulin M levels are low and immunoglobulin A and E levels are elevated. Lymphoreticular malignancies are common. [28]

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a clinical syndrome characterized by neurologic symptoms (fever, renal impairment, thrombocytopenia, hemolytic anemia, and microvascular thrombosis) that result in variable degrees of tissue ischemia and infarction. Large-vessel thrombosis is uncommon. TTP is associated with both familial and acquired factors.

Studies have shown a relationship between the actions of a von Willebrand factor (vWF) metalloprotease, ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, 13) and platelet adherence to the extracellular vascular matrix. ADAMTS13 is a plasma zinc metalloprotease that cleaves vWF in the process of coagulation. A deficiency of ADAMTS13 creates a propensity for increased vWF-platelet aggregation that results in the intravascular thrombosis seen in TTP. While levels of ADAMTS13 are very helpful in a definitive diagnosis, they take days for results in most centers and should not be waited upon to start plasmapheresis. In a clinically suggestive picture, elevated LDH and the presence of schistocytes on peripheral smear are sufficient starting points for emergent treatment.

ADAMTS13 deficiency can be caused by a genetic mutation or the action of autoimmune inhibitors. Several drugs have been implicated in the development of inhibitors and clinical TTP, including cyclosporine A, mitomycin-C, ticlopidine, simvastatin, atorvastatin (Lipitor), and clopidogrel (Plavix). Infection with the human immunodeficiency virus (HIV) has also been associated with TTP.

Therapeutic plasma exchange with 40 mL fresh frozen plasma (FFP)/kg of body weight is the treatment of first choice in acute TTP and thrombotic thrombocytopenic purpura–adult hemolytic uremic syndrome (TTP-HUS). FFP replenishes the deficient ADAMTS13, while plasma exchange removes some of the pathogenic autoantibodies and endothelial-stimulating cytokines. Octaplas is a pooled plasma (human) blood product that has been treated with a solvent detergent process. This blood product provides a viable alternative to single-donor fresh-frozen plasma and provides a reduced risk of certain viral transmissions.

McCarthy et al have treated more than 160 patients using FFP, solvent detergent (SD), and cryosupernatant as the exchange media. [29] They showed that SD plasma has value in virtually eliminating all allergic reactions during treatment. Approximately 80% of patients respond to plasma exchange therapy.

Rituximab, a monoclonal antibody against CD20 present in B-lymphoid cells, has been successfully used in treating patients with acquired TTP who had failed to respond to plasma exchange.

Severe ADAMTS13 deficiency is specific for idiopathic TTP and identifies a subgroup of good responders to plasma exchange. High-titer ADAMTS13 inhibitors correlate strongly with a high risk of relapsing disease. Knovich et al have developed an ADAMTS13 assay suitable for guiding the treatment of patients with suspected TTP. [30] Recombinant ADAMTS13 may provide specific and more efficacious treatment of patients with TTP. Antiplatelet agents to inhibit the interaction between von Willebrand factor (vWF) and platelets are also being studied. [31]

Reviewing the outcomes of 56 patients, Marn Pernat et al investigated the efficacy of membrane plasma exchange for the treatment of idiopathic TTP. [32] The patients (36% of whom were found to have renal impairment) underwent membrane plasma exchange 1-2 times daily until their platelet count normalized, with 1-1.5 plasma volumes (3606 +/- 991 mL) being replaced with FFP during each procedure. Overall, 1066 plasma exchange procedures were performed in this group of patients, with each patient undergoing an average of 19 +/- 17 procedures. [32] The authors reported that 52 (93%) of the patients had an excellent response to treatment, with 48 (86%) of them experiencing complete remission (platelet count >100 x 109/L).

Four patients died after having received only 1-3 procedures; 6 patients who had had a complete remission suffered 1-5 relapses annually during the follow-up period, 1 of whom died of acute hemolytic reaction while undergoing tapering of plasma exchange procedures [32] . In addition, 3 patients required additional splenectomy. The authors concluded that the use of plasma exchange with FFP "as a mandatory, up-to-date therapy" is supported by their data. [32]

Heritable connective-tissue abnormalities and/or vascular malformations

A third group of vascular hemostatic disorders includes those associated with hereditable connective-tissue abnormalities and/or vascular malformations. [33] These disorders are considered hemostatic, in part because of their predilection for bleeding or thrombosis and for the development of consumptive coagulopathies after either hemorrhage or excision. [34]

Two inherited connective-tissue disorders have major cardiovascular complications: Marfan syndrome and Ehlers-Danlos syndrome type IV. [35]

Marfan syndrome results from mutations in the FBN1 gene, which encodes fibrillin-1, an extracellular matrix component found in structures called microfibrils. Ehlers-Danlos syndrome type IV results from mutations in the COL3A1 gene, which encodes the polypeptides in type III collagen.

Marfan syndrome remains primarily a clinical diagnosis. Biochemical analysis of the amount of type III collagen produced by dermal fibroblasts has proven to be a powerful diagnostic test for Ehlers-Danlos syndrome type IV. The most common manifestations of Ehlers-Danlos syndrome are hyperextensible skin and joints, skin fragility, and reduced wound-healing capability. Collagen disorders are associated with congenital intracranial aneurysms, accounting for approximately 5% of these cases. [36] Patients with Ehlers-Danlos syndrome may present with sudden, massive gastrointestinal hemorrhage. [37]

Freeman and colleagues reported 95 complications from Ehlers-Danlos type IV syndrome.Their series included 45 subjects with vascular problems, including 22 with spontaneous intraabdominal hemorrhage. [38] They recommend treatment with nonoperative (ie, angiographic) interventions as a first step, followed by simple vessel ligation.

Cavernous hemangiomata and hereditary hemorrhagic telangiectasias can be loosely added to this group. Cavernous hemangiomata are vascular tumors composed of large dilated blood vessels, often containing large amounts of blood. They can be found in the brain, skin, subcutaneous tissue, and many abdominal viscera, particularly the liver, spleen, and pancreas. [39]

Hereditary hemorrhagic telangiectasia is an autosomal dominant inherited disease associated with various vascular malformations. [40] The disease is caused by defects of transmembrane protein components of the receptor complex for transforming growth factor-beta (TGF-beta). Vascular malformations can be found in the pulmonary, spinal, intracerebral, and hepatic circulation. They vary in size and may cause no symptoms, or they may be responsible for hemorrhage, thrombosis, cardiac insufficiency, portal hypertension, and hepatic encephalopathy secondary to shunting. Hepatic involvement can usually be confirmed with color duplex ultrasonography. Embolization or ligation of the malformations is the main therapeutic strategy.

Shwartzman phenomenon

The Shwartzman phenomenon is defined as local or systemic vasculitis caused by a 2-stage reaction. An initial exposure to endotoxin produces intravascular fibrin thrombi whose clearance results in reticuloendothelial blockade. This prevents the clearance of thrombi generated by a second exposure to endotoxin, polyanions, glycogen, or antigen/antibody complexes, which leads to tissue necrosis and/or hemorrhage.

In pregnancy, gram-negative septicemia during delivery or abortion may serve as the first or provocative encounter. [41] The Shwartzman phenomenon is often associated with sepsis, the systemic inflammatory response syndrome (SIRS), and DIC.

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Protein C, Protein S, Antithrombin III, and Factor V Leiden Deficiencies

Antithrombin III, protein C, and protein S are all essential components of the coagulation process. All are synthesized by the liver and have a half-life in the range of 4-6 hours. Activated antithrombin III is a major inhibitor of thrombin and factor Xa, with smaller effects on factors IX, XI, and XII. Antithrombin III binds to the endothelial cell surface (proteoglycan heparan sulfate) in the presence of injury. It forms a subendothelial cell matrix that neutralizes thrombin by complexing with it. Antithrombin III serves as a cofactor for exogenous heparin, increasing its activity 1000- to 10,000-fold. [42]

Protein C and S are vitamin K–dependent factors that participate in the thrombomodulin–protein C system. Thrombomodulin and thrombin form a complex on the endothelial cell plasma membrane in response to injury, with activated protein S serving as a cofactor. This complex attracts and binds protein C in the presence of calcium ion to produce activated protein C (aPC). aPC inactivates factors Va and VIIIa, thus halting the coagulation cascade. It also neutralizes plasminogen-activator inhibitor I, thereby facilitating fibrinolysis. Deficiency of the naturally occurring anticoagulant proteins antithrombin III, protein C, and protein S, in addition to aPCR due to the factor V Leiden gene mutation, are associated with inherited thrombophilia.

All of these deficiencies may lead to thrombophilia. Clinical thrombophilia is defined as an early thromboembolic episode (occurring before age 50 y), spontaneous thrombosis, recurrent thrombosis, unusual site of thrombosis, family history of thrombotic episodes, or coumarin-induced skin necrosis complications. [43]

Such patients may have an isolated or combined inherited deficiency in the proteins involved in coagulation. The diagnosis is confirmed by identification of an isolated or combined inherited coagulant deficiency. All affected patients with inherited thrombophilia are at risk of developing thromboembolic disease ranging from mild, superficial venous thrombosis to lethal pulmonary embolism.

Martinelli et al compared the lifetime probability of developing thrombosis, the type of thrombotic symptoms, and the role of circumstantial triggering factors in 723 first- and second-degree relatives of 150 index subjects with different thrombophilic defects. [44]

They found higher risks for thrombosis for subjects with antithrombin (risk ratio [RR], 8.1; 95% confidence interval [CI], 3.4-19.6), protein C deficiency (RR, 7.3; 95% CI, 2.9-18.4), or protein S deficiency (RR, 8.5; 95% CI, 3.5-20.8) compared with those with factor V Leiden deficiency (RR, 2.2; 95% CI, 1.1-4.7) or with individuals with normal coagulation. The risk of thrombosis for subjects with factor V Leiden deficiency was lower than that for subjects with any of the 3 other coagulation defects (RR, 0.3; 95% CI, 0.1-1.6), even when arterial and superficial vein thromboses (SVTs) were excluded and the analysis was restricted to deep vein thrombosis (DVT) (RR, 0.3; 95% CI, 0.2-0.5). No association was found between coagulation defects and arterial thrombosis.

The most frequent venous problem was DVT with or without pulmonary embolism—90% in antithrombin III deficiency, 88% in protein C deficiency, 100% in protein S deficiency, and 57% in factor V Leiden deficiency—but SVT was also common with the latter deficiency (43%). Approximately 50% of subjects had a predisposing condition for thromboembolism, regardless of which deficiency was present. Factor V Leiden deficiency is associated with a relatively small risk of thrombosis, lower than that for antithrombin, protein C, or protein S deficiencies. In addition, individuals with factor V Leiden deficiency develop less severe thrombotic manifestations, such as SVT. [44]

Estimates of the frequency of these defects in a population with venous thrombosis place antithrombin III deficiency at 0.5-4.9%, protein C deficiency at 1.4-8.6%, and protein S deficiency at 1.4-7.5%. [45]

Factor V Leiden deficiency is the most common disorder and is found in 12-40% of white populations. Protein C and S deficiencies may be more prevalent in Asian populations than in white.

Miyata et al identified 54 people with protein C deficiency by screening approximately 26,800 patients. This represents an observed prevalence of 1 case per 500 patients. [46] These researchers also found that 34 patients with protein C deficiency had earlier onset of acute myocardial infarction and atherothrombotic cerebral infarction compared with healthy patients. Their study suggests that congenital protein C deficiency contributes to an earlier onset of arterial occlusive diseases in Japanese subjects.

Suehisa and colleagues studied 113 consecutive patients with DVT, finding antithrombin III, protein C, and protein S deficiencies. [47] Among patients with DVT, 32 (28.3%) were deficient in antithrombin III (1.77%), protein C (7.96%), and protein S (17.7%). Ten of the 392 healthy Japanese subjects had protein S deficiency (n = 8, 2.02%) or protein C deficiency (n = 2, 0.5%). The frequency of protein C and S deficiencies in patients with DVT was 15.6 and 7.38 times the control population frequency, respectively, and this difference was statistically significant (P < .05). These data suggest that the Japanese population has a high frequency of protein C and S deficiencies.

In Taiwan, Shen and colleagues noted that prothrombin G20210A and factor V Leiden mutations were not found in 113 thrombophilic Chinese patients. [48] Only protein C and S deficiencies were significantly associated with increased risk for the development of thrombosis with an odds ration (OR) of 10.6 and 6.7, respectively. These findings suggest that protein C and protein S deficiencies are the most important risk factors for thrombosis in venous thrombophilic patients of Chinese extraction. The true prevalence of these hereditary disorders is unknown because of the high variability of clinical presentation. [49]

Deficiencies of antithrombin III, protein C, and protein S are defined as an absence or a reduced level of protein leading to an increased risk for thrombosis. These deficiencies can be congenital or acquired. [50] The former are caused by partial or complete gene deletions, replacements, and rearrangements. [51]

Deficiencies take several forms and may be quantitative or qualitative. The following have been described: (1) loss of the entire molecule, (2) diminution of activity only with normal concentration, (3) normal activity and concentration but with a decreased sensitivity to heparin (antithrombin III), (4) diminished production of antithrombin III, (5) increased loss of antithrombin III, or (6) an increased consumption of the inhibitor. [52]

Antithrombin III deficiency should be considered in any patient who cannot be adequately anticoagulated on heparin or who develops thrombosis while on heparin in the absence of heparin-induced thrombocytopenia. Fresh frozen plasma or highly purified concentrates should be administered before starting heparin for patients needing anticoagulation. Adequate antithrombin substitution is lifesaving in patients whose cases of DIC are caused by septic or traumatic shock. Protein C and S deficiencies follow a similar pattern and have similar clinical manifestations.

Factor V has both procoagulant and anticoagulant properties. Activated factor V stimulates the formation of thrombin, whereas anticoagulant factor V acts as a cofactor for aPC in the degradation of factor VIII and factor VIIIa, thereby reducing thrombin formation. High procoagulant factor V levels may enhance prothrombinase activity and increase the risk of thrombosis. A Leiden mutated factor V is resistant to aPC lysis compared with the wild type. Resistance to aPC is the most common inherited hypercoagulable state associated with venous thrombosis. Low anticoagulant factor V levels can reduce aPC cofactor activity in the inactivation of factor VIII (aPCR phenotype), which might also promote thrombosis. Low factor V levels in combination with factor V Leiden could lead to a more severe aPCR phenotype (pseudohomozygous aPCR). [53]

In 1998, Girolami et al proposed an updated classification that separated factor V deficiencies into those that cause hemorrhage and those that cause thrombosis. [54] Their classification of hemorrhagic disorders included (1) homozygous and heterozygous "true" factor V deficiency and (2) combined factor V and factor VIII deficiencies.

The mutation is found mostly in whites, but the prevalence of the mutant factor V allele (FV:Q506) varies between countries. It is found to be highly prevalent (up to 15%) in Scandinavian populations and is found in 20-60% of white patients with thrombosis. [55]

Samama et al studied 125 family members with the clinical characteristics of thrombophilia associated with heterozygous or homozygous factor V Leiden mutation. [56] Factor V mutation was present in the 51 propositi and in 84 of 125 family members (81 heterozygous, 3 homozygous). Venous thrombosis was observed in all the propositi, in 17 of the 84 family members with the mutation, and in 6 of the 41 with a normal aPCR test finding and no mutation. An associated protein C or protein S deficiency was present in 5 families (10%).

The most frequent clinical manifestations of aPCR or factor V Leiden deficiency are SVT or DVT and/or pulmonary embolism and thrombosis at an unusual site (cerebral, mesenteric, or central retinal vein). A causal relationship is frequently difficult to demonstrate. A precipitating factor was observed in 84% of cases, and a recurrent thrombotic episode occurred in 50% of those affected in Samama et al's study. The risk of thrombosis associated with pregnancy was high in the postpartum period, especially in homozygous women. In homozygous patients, markers of coagulation activation are frequently elevated in those who are untreated. In heterozygous true factor V deficiency, both activity and antigen are about 50% of normal. [57]

Laboratory screening for aPCR is performed by functional tests measuring the effect of aPC on aPTT in plasma containing a heparin neutralizer. Second-generation tests that reduce screening errors are now available. [58]

The question of who should be screened remains unsettled. Marz et al have taken an inclusive approach to causes of venous thromboembolism (VTE) in describing the interactions between genetic and environmental causes of this disease state. [59] They propose that inborn factors that cause a predisposition to thrombosis are present in most patients who develop VTE.

The relatively rare defects of antithrombin III, protein C, and protein S deficiencies are found in 15-20% of thrombophilic families, in contrast to the common genetic polymorphisms of procoagulant molecules, factor V Leiden, and the prothrombin 20210 A allele. The results of Marz and colleagues' studies of factor V Leiden and prothrombin 20210 A indicate that many symptomatic individuals have more than one (genetic and/or environmental) risk factor. Important nongenetic risk factors include age, tissue damage, oral contraception, pregnancy, obesity, and lack of physical activity.

A thrombophilia workup including the above-discussed laboratory tests is warranted only in young patients with unusual sites of first thrombosis, to decide duration of anticoagulation, use of oral contraceptives, and family counseling. Indiscriminate testing is not warranted.

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Disseminated Intravascular Coagulation

DIC is a syndrome characterized by an alteration in the elements involved in blood coagulation due to their use/destruction in widespread blood clotting within the vessels. It may be caused by a wide variety of disorders, including hemorrhage, trauma, sepsis, toxic shock syndrome, endotoxin release, abruptio placentae, and amniotic fluid embolism. [60] Sepsis is the most common cause of DIC.

Etiology

The etiology and progression of DIC are multifactorial and are characterized by defects in the protein C system and in the antithrombin and tissue-factor inhibitor pathways. Tissue factor–dependent activation of coagulation, defective physiological anticoagulant pathways, and impaired fibrinolysis caused by elevated levels of plasminogen activator inhibitor type 1 (PAI-1) can all lead to DIC. Release of tissue factor from endothelial cells or other circulating cells is the most common initiating event. Bacterial factors also release tissue factor as well as proinflammatory and anti-inflammatory cytokines. Tumor necrosis factor (TNF) and interleukin 8 (IL-8) increase the inflammatory response, while IL-10 inhibits it. IL-1 beta, IL-12, IL-2, G-CSF, and IFN-gamma have all been reported to induce coagulation. IL-4, IL-13, and TGF-beta have anticoagulant activity.

These imbalances all promote the development of DIC. Persistence of the triggering agent (eg, a septic locus) leads to a consumption coagulopathy with loss of fibrinogen and platelets and the potential for diffuse bleeding. Failure of the fibrinolytic system elicits deposition of microvascular fibrin and multisystem organ failure (MSOF). [61]

Vervloet and colleagues (University Hospital, Amsterdam, the Netherlands) are proponents of the theory that DIC is an imbalance between coagulation and fibrinolysis mediated by various cytokines and caused by increased levels of PAI-1. [62] Increased levels of PAI-1 produce a procoagulant state characterized by thrombin generation in excess of plasmin and impaired fibrin degradation, leading to widespread fibrin deposition. Thrombin generation proceeds via the extrinsic tissue factor/factor VIIa route simultaneous with consumption of the natural coagulation inhibitors antithrombin III, protein C, and protein S increases. Although levels of plasminogen activator antigen are increased, its activity is almost completely inhibited by PAI-1. High plasma levels of thrombin-antithrombin (TAT) complex can be found.

The Amsterdam investigators found that increased PAI-1 levels are associated with poorer outcome and increased severity of MSOF in patients with DIC from sepsis as well as other causes. Hardaway and Vasquez believe that DIC may be initiated by release of a thrombogenic aminophospholipid from dying tissue or bacterial cells. [63] Coagulation abnormalities secondary to DIC are coupled to the inflammatory response, which aggravates vascular permeability, inflammation, and cell damage in tissues. This combination of events leads to MSOF and death. DIC may produce adult respiratory distress syndrome through the mechanism of intravascular fibrin formation, vessel occlusion, and localized hypoxia. [64]

In Japan, Watanabe and colleagues measured plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI) activity and antigen in patients with DIC in a study designed to examine the role of hypofibrinolysis in this disorder. [65] Both TAFI activity and antigen levels were significantly below reference ranges in patients with DIC. Decreases in TAFI activity were inversely correlated with increases in plasma TAT III complex and D-dimer, suggesting that TAFI activity is reduced by thrombin generation and consumption of coagulation factors. TAFI activity levels were not correlated with fibrinogen, plasma alpha2-plasmin inhibitor complex, and tissue plasminogen activator (TPA)/PAI-1 complex levels, thus supporting a role for TAFI as a secondary modulator of fibrinolysis.

Epidemiology

Okajima et al examined the incidence, clinical presentation, and underlying disorders associated with DIC in a series of 1882 subjects. Of these, 204 were diagnosed as having DIC, for an overall incidence of 10.8%. [66] Malignancies led the list of underlying disorders with 33.8% of subjects having solid tumors and 12.7% having hematologic malignancies. Subjects with aortic aneurysm (10.8%), infections (6.4%), unspecified postoperative complications (4.4%), liver disease (2.9%), obstetric disorders (2.5%), and miscellaneous diseases (26.5%) completed the diverse list.

Clinical manifestations of subjects with DIC varied, depending on underlying disease. The large majority of those with aortic aneurysm (95.5%) or postoperative complications (88.9%) had no clinical signs of DIC. Bleeding was observed in all obstetrical patients and in 32-50% of those with liver disease, hematological malignancies, and solid tumors. Organ failure was observed in up to 33.3% of subjects who had DIC with liver disease, hematological malignancies, and solid tumors. Although all of the subjects with obstetric disorders had bleeding, only 20.0% had organ failure. In contrast, although only 15.4% of subjects with infections had bleeding, 76.9% of these had organ failure.

Chuansumrit et al (Mahidol University, Bangkok, Thailand) found a similar broad spectrum of underlying diseases in 100 pediatric patients with DIC. [67] Forty-five subjects were neonates with a mean age of 12.6 days, and 55 were infants, children, and adolescents with a mean age of 6 years and 3 months. Most subjects (91.5%) had complicated underlying conditions, which included congenital anomalies, prematurity, malignancies, hematological disorders, and various diseases. The most commonly found initiator of DIC was gram-negative septicemia. Bleeding and thromboembolic events were found in 59.4% and 19.8% of participants, respectively.

Asakura et al examined the relationship between fibrinolytic enhancement and development of MSOF in 69 subjects with DIC. [68] Those with both DIC and MSOF had higher levels of TPA antigen and PAI antigen and more depressed levels of plasma alpha2-plasmin inhibitor complex (PIC) and fibrin/fibrinogen degradation products than those without MSOF.

Diagnosis

The diagnosis of DIC is based on both clinical suspicion of DIC and a combination of laboratory test findings. Patients with the following known underlying causes should be carefully observed for indications of the development of DIC (eg, microthrombi, bleeding):

Underlying causes of DIC sepsis/infection are as follows:

  • Malignancy
  • Trauma
  • Aortic aneurysm
  • Cerebral injury
  • Hepatic surgery
  • Burn injury
  • Hypothermia
  • Massive transfusion
  • Prolonged surgery

Evidence of ongoing consumption of coagulation proteins from laboratory testing includes decreasing fibrinogen levels and platelet counts. PT and aPTT may both be prolonged. Peripheral smear may show schistocytes. Increasing plasma levels of D-dimer, fibrinogen split products (FSP), and soluble fibrin monomer (FM), are found as DIC progresses. Elevated D-dimer levels reflect both thrombin and plasmin production. [61] These studies must be repeated to confirm the diagnosis of DIC and to monitor therapeutic progress. [69]

Circulating factors can be used as markers of prognosis in DIC. In 1999, Kotajima et al showed that levels of plasma thrombomodulin, a high-affinity thrombin receptor on vascular endothelial cells, were significantly higher in nonsurvivors of DIC compared to survivors (thrombomodulin 3.1+/-1.52 FU/mL vs 8.1+/-3.89 FU/mL). [70]

Treatment

The treatment of DIC can be divided into the following components: (1) treatment of the underlying disorder, (2) supportive management of bleeding complications, and (3) treatment aimed at the coagulation process.

The triggering underlying disease must be treated aggressively. This may require surgical drainage of an abscess or necrotic tissue, antibiotic therapy, control of temperature, volume replacement, etc. Early recognition and treatment of DIC is the key to success, so a high index of clinical suspicion must be maintained.

Continued DIC is characterized by a consumption coagulopathy of platelets. Ongoing bleeding or rapid hemorrhage may lead to anemia. These deficiencies can be corrected by administration of platelet transfusions, cryoprecipitate (to replete fibrinogen) and FFPs.

Heparin may be cautiously used if thrombosis is the predominant manifestation, although this is easier said than done in the presence of ongoing bleeding.

A trial of low molecular weight dalteparin compared to unfractionated heparin showed less bleeding and better organ system scores, but it demonstrated no survival benefit. [71] Generally, the earlier treatment is initiated, the better the patient's prognosis. [61]

The utility of antithrombin III treatment for DIC is still unknown. A meta-analysis of 122 subjects included in 3 placebo-controlled, randomized studies of antithrombin III therapy for severe sepsis showed a 22% reduction in 30-day all-cause mortality and a reduction in the length of stay in the intensive care unit in the antithrombin III–treated group. Although antithrombin III treatment significantly decreased the risk of death in one study, the aggregate results were not statistically significant. [72, 73, 74] Hoffmann and colleagues recently reported that a 14-day course of antithrombin administration in septic patients normalized global coagulation tests and increased prothrombin activity as well as fibrinogen concentration, reflecting less coagulation factor consumption when compared with untreated controls. Unfortunately, the treatment had no impact on survival. [75]

These trials of coagulation inhibitors have been conducted in patients with sepsis, not DIC per se. Although coagulation inhibitors may be shown to play an important role in selected subgroups of patients, their efficacy and safety remain to be proven. [76]

Recombinant activated human factor VII (rFVIIa) continues to show promise in patients with coagulopathy from trauma, DIC, postpartum bleeding, sepsis, and postoperative hemorrhage. [77, 78, 79, 80] Laffan et al stopped or reduced pancreatitis-associated bleeding in 11 of 12 patients, but the treatment had no impact on overall survival. [81] Lim et al used the drug successfully in 7 patients with amniotic embolism–induced bleeding. [82] These results point out that more controlled trials are needed to understand both the timing and the effective dose of rFVIIa.

Recombinant human thrombomodulin alpha (rTM), which acts as an inhibitor of thrombin, has shown some benefit in thrombosis-predominant patients with DIC, but bleeding remains a concern and use is not widespread. [83]

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Coagulation-impairing Deficiencies

Factor V deficiency

Factor V has both procoagulant and anticoagulant properties. Activated factor V stimulates the formation of thrombin, whereas anticoagulant factor V acts as a cofactor for aPC in the degradation of factor VIII/VIIIa, thereby reducing thrombin formation.

An inherited autosomal recessive deficiency of factor V proaccelerin (or accelerator globulin or labile factor) leads to a rare hemorrhagic tendency known as Owren disease or parahemophilia. The severity of the condition varies from bruising to lethal hemorrhage [84, 85, 86] Both PT and aPTT may be prolonged.

Lak et al identified epistaxis and excessive bleeding after surgery as the most common symptoms in 35 Iranian patients with an inherited factor V deficiency, with plasma levels of 1-10%. [87] More severe symptoms, such as gastrointestinal and central nervous system bleeding, were rare. The severity of bleeding symptoms was only partially related to the degree of factor V deficiency in plasma. Acquired inhibitors of factor V are rare causes of clinical bleeding, with severity ranging from mild to life threatening.

No Factor V concentrate is available yet. Fu et al were successful using a combination of factor replacement, chemotherapy, and plasmapheresis in a patient with spontaneous, life-threatening intracranial bleeding caused by a factor V inhibitor. The patient deteriorated after initial treatment with fresh frozen plasma and platelet transfusions. He was subsequently treated with a combination of plasma exchange and chemotherapy, which led to complete recovery. Ref85}

Combined deficiency of coagulation factor V and factor VIII is an autosomal recessive disorder observed in a number of populations around the world. However, this disease appears to be most common in the Mediterranean basin, particularly in Jews of Sephardic and Middle Eastern origin living in Israel. [88]

Factor VII deficiency

Factor VII is a vitamin K–dependent glycoprotein essential to the extrinsic pathway of coagulation. Deficiencies may be inherited as an autosomal recessive characteristic or acquired in association with vitamin K deficiency, sepsis, autoantibodies, and inhibitors. [89, 90] The prevalence of congenital deficiency is low, with only 238 individuals with factor VII gene mutations described in the world literature as of 2001 (see the Factor VII Mutation Database). [91]

The predisposition to bleeding is variable and to some extent depends on the amount of plasma factor VII activity, although this correlation is poor. [92] In congenital factor VII deficiency, the clinical picture is related to the levels of factor VII coagulant activity. Menorrhagia and metrorrhagia in females and mucosal bleeding and hemarthrosis in both sexes are the most frequent manifestations. Individuals homozygous for the mutation who have complete absence of factor VII activity in plasma usually die shortly after birth because of severe hemorrhage.

This defect produces prolonged PT, reduced factor VII activity, and normal aPTT. [93] True deficiencies are characterized by very low factor VII activity and low factor VII antigen Other patients may have normal antigen levels but low activity. [94]

Clinical symptoms and factor VII activity levels in plasma are rather poorly correlated. Patients may have prolonged PTs and a mixing study is helpful as rapid, sustained correction suggests a factor VII deficiency, but the final diagnosis is established by quantitative factor VII assays. Treatment consists of factor replacement with fresh frozen plasma, prothrombin complex concentrates, or factor VII concentrates. Recombinant activated factor VII is a very useful alternative. Hunault and Bauer have reported several successfully treated patients. [92] Because of the short half-life of factor VIIa, repeated doses must be administered.

Factor X deficiency

Factor X deficiency is a blood coagulation disorder usually inherited as an autosomal recessive trait, though it can be acquired. This deficiency is characterized by defective activity in both the intrinsic and extrinsic pathways, impaired thromboplastin time, and impaired prothrombin consumption. Factor X circulates as a serine protease that is activated at the point of convergence of the intrinsic and extrinsic coagulation pathways. Activated factor Xa is involved in macromolecular complex formation with its cofactor factor Va, a phospholipid surface, and calcium to convert prothrombin into thrombin. [95] Both PT and aPTT are prolonged.

Factor X deficiency may be acquired in patients with light chain–related amyloidosis. This acquired disorder appears to be secondary to adsorption of factor X to the amyloid fibrils. [96, 97] In 1981, Greipp et al reviewed 30 cases of patients who had amyloidosis with factor X deficiency. [98] Modest deficiency of factor X was often associated with severe bleeding. In many cases, clinical bleeding could not be accounted for by deficiency of factor X alone, leading the authors to believe that coexistent hemostatic defects probably contributed to the bleeding. Testing with Russell viper venom may demonstrate an immunoglobulin G inhibitor that selectively inhibits factor X activation. [99]

Treatment of acquired factor X deficiency is difficult. In 2001, Boggio and Green reported that control of bleeding with plasma or prothrombin complex concentrates is not completely successful. [100] Smith and colleagues had similar problems in 2 patients, which led them to resort to daily therapeutic plasma exchange with concomitant administration of intravenous immunoglobulin and steroids. [99] This therapy produced a rapid increase in factor X levels, which controlled the bleeding, followed by gradual recovery of normal factor X levels and correction of coagulation times. Splenectomy eliminates the acquired factor X deficiency in amyloidosis, but control of operative bleeding may require recombinant factor VII.

Factor XI deficiency

Factor XI deficiency is a congenital deficiency of blood coagulation factor XI (known as plasma thromboplastin antecedent [PTA] or antihemophilic factor C) resulting in a systemic blood-clotting defect called hemophilia C or Rosenthal syndrome, which may resemble classic hemophilia.

Factor XI is a key component of the intrinsic pathway of blood coagulation in vitro, but its exact role in vivo is uncertain. Factor XI is activated by thrombin and may participate in clot formation once coagulation has been initiated by other mechanisms. The risk of bleeding in factor XI deficiency depends on the severity of the deficiency. Additional coexisting abnormalities of hemostasis, such as von Willebrand disease, may also be responsible for variations in clinical presentation, particularly in individuals with mild factor XI deficiency. [101, 102]

Approximately 40-50% of all persons lacking factor XI are of Ashkenazi Jewish extraction. [103] Factor XI deficiency may be considered in patients evaluated for hemorrhage or unexplained, prolonged aPTT or through family or other genetic studies. Women with factor XI deficiency are prone to menorrhagia and to bleeding complications after childbirth. [104, 105] Individuals with factor XI deficiency need careful planning for elective surgery and dental extractions. Fresh frozen plasma, fibrin glue, antifibrinolytic drugs, desmopressin, and factor XI concentrates have all been used successfully. Factor XI concentrate is usually reserved for younger patients with severe deficiency because its use in older patients has been associated with thrombotic phenomena.

Factor XII deficiency

Factor XII deficiency is defined as an absence or reduced level of blood coagulation factor XII (Hageman factor). Factor XII initiates the intrinsic coagulation cascade and is linked to the fibrinolytic, kallikrein-kinin, and complement systems. [106] It promotes the conversion of factor XI to its activated form. Factor XII deficiency typically occurs in the absence of a patient or family history of hemorrhagic disorders and is marked by prolonged clotting time.

Halbmayer et al have estimated the prevalence of severe and mild factor XII deficiency to be 1.5-3%. [107] This group has identified an association between factor XII deficiency and coronary artery disease. Measurements of plasma factor XII activity, fibrinogen, and lipoprotein in 426 consecutive patients with coronary heart disease awaiting cardiac surgery found 44 (10.3%) were moderately deficient in factor XII (factor XII activity, 17-50%; antigen, 15-57%). The prevalence of factor XII deficiency was significantly higher (P < .0001) among patients with coronary heart disease than among 300 similarly evaluated healthy blood donors (2.3%).

Factor XII deficiency has not been linked to any significant hemorrhagic diatheses. The disorder may be considered in patients with prolonged aPTT, normal PT, normal bleeding time, and no clinical history of bleeding. Once thought likely, the deficiency can be confirmed by normalization of aPTT with plasma component therapy and by factor assay.

Factor XII deficiency has clinical significance when attempts are made to heparinize individuals who have this condition. Routine coagulation tests used during cardiopulmonary bypass return abnormal findings in patients with factor XII deficiency and are useless for monitoring anticoagulation in these patients. Alternative monitoring systems, such as chromogenic heparin assay, citrated thrombin time, and recalcified thrombin time, must instead be used. [108]

Factor XIII deficiency

Factor XIII deficiency is a decrease or absence of factor XIII (fibrin-stabilizing factor [FSF]) that prevents blood-clot formation and results in a clinical hemorrhagic diathesis. Factor XIII is an enzyme found in plasma, platelets, and monocytes. In plasma, factor XIII has 2 subunits: the a subunit, which is the active enzyme and the b subunit, which is a carrier protein. [109] Activated factor XIII stimulates cross-linkage of fibrin as a means of stabilizing clot.

A bleeding patient with both normal PT and aPTT should raise the suspicion.

Congenital factor XIII deficiency is a severe autosomal recessive bleeding disorder associated with a characteristic pattern of neonatal hemorrhage and lifelong bleeding diathesis. Untreated patients have a high mortality rate. Even relatively minor trauma can be followed by prolonged and recurrent bleeding. Intracranial hemorrhage is a frequent complication. [110] The disorder affects both sexes, and bleeding may occur during pregnancy. [111] Acquired factor XIII deficiency has been described in HSP, various forms of colitis, erosive gastritis, and some forms of leukemia. Inhibitors to factor XIII are rare. [112] Treatment of factor XIII deficiency requires lifelong prophylactic therapy with at least monthly infusions of factor XIII concentrate, even during pregnancy. [110, 111] .

Cryoprecipitate is rich in factor XIII. A new recombinant factor XIII subunit a is being tested. [113]

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