Copyright (c) 2005-2008, PathologyOutlines.com, Inc.
Reviewed by Kendall Crookston, MD, PhD (see reviewers page)
Last revised 10 June 2008
Last major update July 2005
Bold and underlined topics are hypertext links within this document or to references
Table of Contents-Coagulation
Primary references, hemostasis-general, normal hemostasis, intrinsic pathway, extrinsic pathway, common pathway, protein C/S, thrombomodulin, antithrombin, fibrinolysis pathway, contact system
Bleeding disorders: general, laboratory approach
Acquired bleeding disorders: acute phase reaction, acquired dysfibrinogenemia, acquired von Willebrand’s disease, amyloidosis, bovine coagulation factor inhibitors, DIC, factor V inhibitor, factor VIII inhibitor, factor IX inhibitor, liver dysfunction, lupus anticoagulants, proteinuria, Vitamin K deficiency/warfarin
Hereditary bleeding disorders: general, algorithm for workup, factor I (fibrinogen) deficiency, factor II (prothrombin) deficiency, factor V deficiency, factor VII deficiency, factor VIII deficiency (hemophilia A), factor IX deficiency (hemophilia B), factor X deficiency, factor XI deficiency, factor XII deficiency, factor XIII deficiency, high molecular weight kininogen deficiency, prekallikrein deficiency, von Willebrand’s disease
Therapy related coagulopathies: warfarin, danaparoid, heparin, heparin-low molecular weight, hirudin, thrombolytic therapy
Acquired thrombophilia / hypercoagulopathies: general, antiphospholipid antibodies, heparin induced thrombocytopenia
Hereditary thrombophilia / hypercoagulopathies: general, activated protein C resistance / factor V Leiden, antithrombin deficiency, dysfibrinogenemia, elevated coagulation factors, heparin cofactor II deficiency, hyperhomocysteinemia, protein C deficiency, protein S deficiency, prothrombin gene mutation (G20210A), sickle cell disease
Coagulation laboratory tests: general, quality assurance, abnormal PT and PTT, activated clotting time, activated protein C resistance, anticardiolipin antibodies, antiplasmin, antithrombin, bleeding time, clot retraction, cryoglobulin / cryofibrinogen, D-dimer, ecarin clotting time, factor assays, factor I (fibrinogen) assay, factor V Leiden, factor VII assay, factor VIII assay, factor VIII inhibitor, factor IX assay, factor Xa assay, factor XI assay, factor XIII assay, heparin induced thrombocytopenia, heparinase, high molecular weight kininogen, homocysteine, hypercoagulation panel, INR, International sensitivity index, low molecular weight heparin, lupus anticoagulant, mixing studies, plasminogen assay, plasminogen activator antigen-1, platelet aggregation studies, platelet antibodies, platelet hyperaggregation studies, prekallikrein assay, protein C assays, protein S assays, prothrombin gene 20210A, PT, PTT, reptilase time, thrombin time, tPA, vWF testing-general, vWF antigen analysis, vWF activity, vWF multimer analysis
Archives of Pathology and Laboratory Medicine (Archives), January 1976 to July 2005
Journal of Clinical Pathology, January 2001 to July 2005
Henry: Clinical Diagnosis and Management by Laboratory Methods, 2001 (20th edition)
Massachusetts General Hospital coagulation handbook
Journal search terms: coagulation
Please refer to these primary references for more detailed discussions and photographs
Involves formation of blood clots to stop bleeding from damaged vessels, and activation of natural anticoagulation and fibrinolytic systems to limit clot formation to sites of injury
Bleeding disorders are due to defects in clot formation or overactive fibrinolytic systems
Hypercoagulability disorders are due to defects in anticoagulant system or underactive fibrinolytic systems
Initial step is formation of platelet plug to stop bleeding from damaged vessel
Then, platelet plug is reinforced by fibrin clot
Then, fibrin clot is stabilized by activated factor XIII, which cross-links fibrin strands
Fibrin clot may occur via either intrinsic or extrinsic pathway (or both), though in vivo it occurs via a hybrid model
Coagulation factors in intrinsic or extrinsic pathway assemble on surface of activated platelets, which are usually at site of vascular injury
Many coagulation reactions also require calcium as a cofactor
Note: “a” after factor number indicates “activated”
Factor I: fibrinogen
Factor II: prothrombin
Factor III: tissue thromboplastin (tissue factor and phospholipid)
Factor IV: ionized calcium
Factor V: occasionally called labile factor or proaccelerin
Factor VI: unassigned
Factor VII: occasionally called stable factor or proconvertin
Factor VIII: antihemophilic factor
Factor IX: plasma thromboplastin component, Christmas factor
Factor X: occasionally called Stuart-Prower factor
Factor XI: occasionally called plasma thromboplastin antecedent
Factor XII: Hageman factor
Factor XIII: fibrin-stabilizing factor
Charts: coagulation cascade #1; #2
Involves factors VIII, IX, XI, XII (Hageman factor), prekallikrein, high molecular weight kininogen
Merges with extrinsic pathway into common pathway
Activated when factor XII binds to negatively charged “foreign” surface exposed to blood
Then sequentially activates factors XI, IX, X, then factor II (prothrombin to thrombin), which converts fibrinogen to fibrin (see common pathway, below)
Once extrinsic pathway is inhibited by TFPI-Xa complex (see extrinsic pathway), factor VIIIa / IXa complex becomes dominant generator of factor Xa, thrombin and fibrin
Factor XIIa also converts prekallikrein to kallikrein, which activates more factor XIIa; both require high molecular weight kininogen as cofactors
Kallikrein also releases bradykinin from high molecular weight kininogen, which causes vasoconstriction
Charts: intrinsic pathway
Involves tissue factor (TF), originally considered “extrinsic” to blood since it is present on cell surfaces not normally in contact with (i.e. extrinsic to) the circulatory system
The primary mechanism of the coagulation pathway in vivo is tissue factor binding to activated factor VII (factor VIIa)
TF-Factor VIIa complex activates factors X and IX (though in vivo it appears to first involve factors VIII and V from the intrinsic pathway, which then activate factors X and IX)
Activated factor IX activates more factor X, with cofactors activated factor VIII, anionic phospholipids (from activated platelets) and calcium
Activated factor X converts prothrombin to thrombin, with activated factor V, anionic phospholipids (from activated platelets) and calcium as cofactors; prothrombin factor 1.2 is released (see common pathway, below)
After initial activation, pathway is inhibited by the binding of tissue factor pathway inhibitor (TFPI) to factor Xa, which inhibits TF-Factor VIIa complex, and further coagulation is dependent on the intrinsic pathway
Merges with extrinsic pathway into common pathway
Charts: coagulation cascade
Involves fibrinogen (factor I), factors II (prothrombin), V, X
Thrombin converts soluble fibrinogen to insoluble fibrin; releases fibrinopeptides A and B; remaining fibrin monomers polymerize to form fibrin; thrombin also binds to antithrombin, which inhibits thrombin to prevent excessive clotting
Thrombin may also activate factor XI (part of intrinsic pathway), factors V, VIII, XIII, XI and platelets
Factor XIII cross links fibrin to increase stability of fibrin clot
Charts: see normal hemostasis (above)
Diagrams: fibrinogen molecule
Protein C / Protein S anticoagulant pathway
Pathway is a physiologic anticoagulant system to limit blood clot formation (i.e. fibrinogen to fibrin conversion) to site of vessel injury
Major anticoagulant systems are protein C and protein S, antithrombin and tissue factor pathway inhibitor (TFPI, see Extrinsic pathway above)
Protein C and S: vitamin K dependent anticoagulant proteins produced mainly in liver (“C” because was third peak to elute from a diethylaminoethyl affinity column)
Activation: endothelial cell protein C receptor binds thrombin-thrombomodulin complex, which activates protein C, which binds to free protein S on endothelial or platelet phospholipids surfaces; this protein C / protein S complex degrades factors Va and VIIIa, which reduces fibrin formation
Activated protein C also indirectly promotes fibrinolysis
60-70% of protein S is bound to and inactivated by C4b binding protein, an acute phase reactant
Clinical note: since C4b increases during pregnancy, the protein S level will routinely fall below the normal non-pregnant range
Diagram: Protein C / Protein S anticoagulant pathway
References: Archives 2002;126:1337
Intrinsic membrane glycoprotein on luminal surface of endothelial cells that binds thrombomodulin and facilitates the activation of protein C
C/T dimorphism at nucleotide 1418 is associated with premature myocardial infarction, but no definite association with venous thromboembolism
Drawings: thrombomodulin protein, flowchart of protein C activation
References: BMC Neurology 2004;4:21
Formerly called antithrombin III
Functions as anticoagulant by inhibiting activated factors II (thrombin), IX, X, XI, XII, kallikrein, plasmin and probably factor VII (all are serine proteases)
Activity is accelerated 1000x by interaction with heparin or heparan sulfate (located on endothelial cells)
Member of serine protease inhibitor (serpin) gene family on #1q23-25
References: Archives 2002;126:1326
Process of degrading the fibrin clot when it is no longer needed
Also prevents extension of clot beyond site of injury
Initiated by tPA (tissue plasminogen activator) or uPA (urokinase-like plasminogen activator), which convert plasminogen to plasmin in the presence of fibrin by cleaving the Arg561-Val562 peptide bond
Plasmin degrades the fibrin clot and intact fibrinogen to soluble fibrin/fibrinogen degradation products (FDP)
Plasmin also inactivates factors Va and VIIIa (as does Protein C and Protein S)
tPA is produced by endothelial cells; its activation of plasminogen is major mechanism for lysis of fibrin clots
Recombinant tPA is used to treat myocardial infarction, stroke and some cases of acute thrombosis
uPA is produced by urine and plasma; keeps renal tracts free of blood clots; also is important for other cell surfaces and initiating nonfibrinolytic activities of plasmin
Excessive fibrinolysis is prevented by plasmin inhibitor (antiplasmin, formerly called alpha2-antiplasmin) and plasminogen activator inhibitor 1 (PAI-1, inhibits tPA and uPA)
PAI-1 is synthesized by hepatocytes and endothelial cells, is present in platelets and plasma; can bind to fibrin and inhibit plasminogen activators tPA and uPA
PAI-1 is an acute phase reactant protein, and may increase 30-50 fold over baseline, possibly immediately inactivating systemically administered tPA
Homozygous deficiency of plasminogen is associated with ligneous conjunctivitis (rare form of chronic pseudomembranous conjunctivitis), and replacement therapy with plasminogen is therapeutic
Neither heterozygous plasminogen deficiency (0.5 to 2.0% of patients with thrombosis) nor tPA deficiency are associated with increased risk of thrombosis
Diagrams: coagulation cascade and fibrinolytic system, diagram
References: Archives 2002;126:1376
Consists of coagulation factors unknown in the 1950’s
Includes factor XII (Hageman factor), prekallikrein (PK; Fletcher factor), high molecular weight kininogen (Williams, Flaujeac or Fitzgerald factor); some authors include factor XI
Made in the liver
Decreased activity is associated with liver disease, hepatic immaturity in newborns, antiphospholipid syndrome, Asian descent (for factor XII)
Homozygous deficiencies are rare, autosomal recessive; cause very long PTT but no bleeding disorders and no definite association with hypercoagulability
Recommended to not measure their activity in routine evaluation of patients with arterial or venous thromboembolism or acute coronary syndromes (Archives 2002;126:1382)
Laboratory testing: homozygous deficiencies cause prolonged PTT; heterozygous deficiencies have near normal PTT; the test for a particular contact factor is based on the ability of the patient’s plasma to correct a prolonged PTT in plasma that is deficient in the factor being tested
Even though the PTT may be decreased by deficiencies of contact factors, this does not necessarily correlate with increased bleeding risk
Bleeding disorders
Clinical history is important:
(a) single site (structural lesion) vs. multiple sites (coagulopathy)
(b) for coagulopathies - hereditary (family history of bleeding or bleeding since childhood) or acquired (no previous bleeding history)
(c) time from “hemostasis challenge” to bleeding symptoms - immediate suggests platelet disorder (inability to form normal platelet plug); late suggests coagulopathy (breakthrough bleeding occurs after platelet plug due to impaired fibrin formation)
(d) physical exam: petechiae (platelet disorders) vs. hematoma or hemarthrosis (coagulation defects) vs. mucous membrane bleeding or bruising (nonspecific)
Bleeding disorders are often classified as defects of primary hemostasis (platelets, vessels, etc.) or of secondary hemostasis (coagulation cascade and its regulation)
Bleeding disorders - laboratory approach
Laboratory tests should be ordered if (a) history or physical exam is suspicious for bleeding disorder or (b) for routine preoperative testing (PT, PTT, platelet count)
See algorithms for prolonged PT, prolonged PTT, abnormal platelet count (platelet chapter) or hereditary bleeding disorder (PT, PTT, and platelet count normal)
References: Crookston, K. P., and Spiess, B.D.; "Coagulation Support in the Perioperative Setting." in Simon: Rossi’s Principles of Transfusion Medicine; 2002 (3rd edition)
Acquired bleeding disorders
Many serum proteins become elevated due to illness, injury, inflammation or stress; also pregnancy
Elevated levels return to normal after condition resolves
Causes increase in fibrinogen, factor VIII, vWF (up to 3x normal levels) and PAI-1 (up to 50x); decrease in PTT, decrease in protein S (due to binding to increased C4b)
Usually caused by liver or biliary tract disease, acute phase reaction, hepatocellular carcinoma or renal cell carcinoma
Due to increased sialylation of fibrinogen’s carbohydrate side changes; this increases its net negative charge, which promotes charge repulsion between fibrin monomers and decreases the rate of fibrin polymerization
Tumor cells may secrete abnormal fibrinogen
Usually does not cause bleeding or thrombosis, but may in alcoholic liver disease
Acquired von Willebrand’s disease
Rare, either spontaneous or associated with hematologic neoplasms or autoimmune disorders
Primary amyloidosis may cause acquired factor X deficiency due to the binding of amyloid to factor X
Also inhibits fibrinogen conversion to fibrin, causing prolongation of thrombin time and reptilase time
Bovine coagulation factor inhibitors
After use of bovine “fibrin glue” to achieve hemostasis, 1.7% develop a clinically significant inhibitor
Some fibrin glue contains bovine thrombin and cryoprecipitate (containing human fibrinogen)
Antibodies may be formed against bovine thrombin, also against bovine factors V, VII, X (Archives 1998;122:887)
Disseminated intravascular coagulation (DIC)
Common, due to massive tissue injury, sepsis or other excessive activation of coagulation system; also pregnancy complications (abruptio placenta, amniotic fluid embolism, acute fatty liver of pregnancy, septic abortion), acute hemolytic transfusion reaction, snake bites, homozygous protein C deficiency, adult respiratory distress syndrome and hyaline membrane disease; chronic causes are cancer, liver disease, aortic aneurysm, retained dead fetus, giant hemangioma or head trauma
Anticoagulant and fibrinolytic systems are activated simultaneously and overwhelmed, leading to disseminated microthrombi and tissue ischemia, consumption of platelets, coagulation factors and natural anticoagulants, and variable bleeding
With malignancy, may get large vessel thrombosis
Activation of fibrinolytic system causes plasmin activation and formation of D-dimers and other fibrin degradation products
Schistocytes (fragmented red blood cells) are formed as red blood cells are severed flowing through fibrin strands
Laboratory: elevated D-dimers and other fibrin degradation products (FDPs), prolonged PT (70% of cases) and PTT (50%), decreasing platelets and fibrinogen (50%), schistocytes (50%); with chronic causes, fibrinogen and platelets may actually be elevated as acute phase reactants; all factors may be variably decreased due to factor activation and consumption
Baseline coagulation studies and serial followup are needed to follow the trends
Note: D-dimer may be falsely positive in HIV+ Castleman’s disease due to interference from monoclonal gammopathy (Archives 2004;128:328)
Treatment: treat underlying disease, transfuse fresh frozen plasma, platelets, cryoprecipitate if bleeding; keep fibrinogen levels above 100 mg/dL with cryoprecipitate or fresh frozen plasma; monitor PT, PTT, platelet count, fibrinogen and possibly antithrombin levels
Case reports: 30 year old woman with DIC due to amniotic fluid embolism (Archives 2002;126:869)
Micro images: schistocyte; amniotic fluid embolism - uterine wall - figure 1: amniotic fluid debris; figure 2: lanugo hair
Diagrams: schematic of DIC
May behave like factor VIII inhibitor in mixing studies, with increasing PTT or PT after 1-2 hours
Most common clinically significant inhibitor; develops in 10-20% of patients with severe hemophilia A after infusion of factor VIII containing products, less often with mild/moderate disease
Rarely arises in patients without hereditary hemophilia, causing acquired hemophilia A (see below)
Causes prolonged PTT; in mixing study, PTT may initially be normal, then increases after 1-2 hours incubation
A nonlinear curve in a factor assay is often a clue to the presence of an inhibitor
Associated with normal PT
In patients with hemophilia A and factor VIII inhibitor, titer of inhibitor often increases after treatment with factor VIII containing products - this does not happen with autoimmune factor VIII inhibitor
Treatment with recombinant factor concentrates appears to lead to more inhibitors than plasma-derived concentrates
Each Bethesda unit of inhibitor indicates a decrease of factor VIII concentration in assay by 50% (1 unit: 100% to 50%; 2 units: 100% to 25%; 3 units: to 12.5%, etc.)
Treatment: porcine factor VIII (if no cross reactivity with inhibitor), prothrombin complex concentrates, FEIBA, recombinant factor VIIa (J Thromb Haemost 2004;2:899), immunosuppression for autoimmune based inhibitors
Nonhemophilic patients (autoimmune based inhibitors)
Incidence of 0.2 to 1 per million population per year
Causes bleeding
50% occur in patients with no known medical problems
Also associated with rheumatoid arthritis, SLE, post-partum; also solid tumors and hematologic malignancies
Laboratory: normal D-dimer and fibrinogen; prolonged PTT not corrected by mixing studies, nonlinear curve on assay for factor VIII
Treatment: recombinant factor VIIa, plasmapheresis (variable success), factor VIII, immunosuppression
References: Archives 2000;124:730
Develops in 2-12% of patients with severe hemophilia B after transfusion of factor IX containing products, less commonly with mild/moderate disease
Rarely arises in patients without hereditary hemophilia, causing acquired hemophilia B
Causes a prolonged PTT, not corrected by mixing studies, and a nonlinear curve on the factor assay
Can quantitate titer of inhibitor
Liver is site of production of most coagulation factors, but response of each factor to liver disease is variable due to differences in biologic half lives and acute phase reactions
PT usually prolonged first, then PTT
Factor VII: shortest biologic half life, often affected earliest with largest decrease in serum level
Clinical note: Factor VII also decreases earliest with warfarin treatment
Factor VIII: may be normal or elevated due to acute phase reaction
Factors XI and XII: long biologic half lives, may be normal until liver disease is advanced
Common
Antibodies against protein-phospholipid complexes
Causes prolonged PTT (not time dependent), increased or normal PT; may interfere with assays for factors VIII, IX, XI and XII without causing a true decrease in factor levels
May be mistaken for a factor VIII inhibitor if dilutions to abnormal factor assays are not done
Not associated with bleeding, except when accompanied by severe thrombocytopenia or acquired factor II deficiency (rare)
May cause factor II deficiency if lupus anticoagulant binds to factor II
May be associated with thrombosis
Case reports: due to phenytoin use (Archives 1987;111:719)
Patients with nephrotic syndrome may have decreased factors XI and XII
Vitamin K deficiency / warfarin use
Both have same molecular mechanism for their effects
Warfarin (coumadin): therapeutic anticoagulant to reduce risk of thromboembolism; impairs regeneration of active vitamin K
Vitamin K: cofactor in carboxylation of glutamic acid residues of factors II, VII, IX and X and protein S and C
Warfarin administration or Vitamin K deficiency cause prolonged PT; severe cases have prolonged PTT also
Vitamin K deficiency: due to fat malabsorption syndromes (vitamin K is a fat soluble vitamin), malnutrition, antibiotics (destroy bacteria producing vitamin K or interfere with vitamin K carboxylation), newborns
Treatment (warfarin overdose - INR > 5.0): fresh frozen plasma or vitamin K; PT should normalize within 12-24 hours
Clinical note: if a large dose of vitamin K is given, then it may be difficult to reach a therapeutic level of warfarin very quickly if the patient continues on warfarin therapy
Treatment (vitamin K deficiency): vitamin K once, then 12-24 hours later, then measure PT (should normalize)
Hereditary bleeding disorders
Hereditary bleeding disorders-general
Acquired factor deficiencies (due to liver disease, DIC, lupus anticoagulants, heparin, warfarin or other anticoagulants) are more common than hereditary factor deficiencies, and should be ruled out first
Heterozygous patients have 30-60% of normal values of affected factors, usually with no or minor bleeding disorder
However, factor I (hypofibrinogenemia or dysfibrinogenemia), X, XI or XIII deficient heterozygotes may have bleeding symptoms
Homozygous deficient patients have <30% of normal values of affected factors
In hemophilia A and B, small differences in factor levels (i.e. 1% vs. 3% vs. 10%) may markedly affect the clinical presentation and course
Hereditary disorders are confirmed by measuring factor levels in relatives
Combined factor deficiencies are very rare
Combined factor V and VIII: autosomal recessive, due to mutation in endoplasmic reticulum-Golgi gene ERGIC 53 on #18 that transports these factors
Combined factors II, VII, IX and X deficiency: due to mutation in gamma-glutamyl carboxylase gene, whose protein carboxylates glutamate residues in vitamin K-dependent coagulation factors
Very rare to have bleeding disorders due to deficiency in PAI-1 or antiplasmin
Symptoms: bleeding associated with surgery, trauma, dental extractions, postpartum, circumcision or umbilical stumps, GI bleeding, intracranial hemorrhage, hemarthrosis or soft tissue hematomas, easy bruising, epistaxis, menorrhagia
Algorithm for workup of hereditary bleeding disorders
Often there is a family history of bleeding disorder
PT, PTT, platelet count often normal
(a) Test for von Willebrand’s disease (most common hereditary bleeding disorder)
Testing for vWD includes Factor VIII activity, vWF antigen, vWF activity (often done by the “ristocetin cofactor” method); these results may lead to vWF multimer assays and blood type (type O patients have reduced vWF activity)
(b) Assays for fibrinogen, platelet aggregation or platelet function assay (e.g. PFA-100), factor XIII, dysfibrinogenemia (thrombin time or reptilase time)
(c) Also assays for factors VIII, IX or XI, even with normal PTT
(d) Factor XIII assay if delayed bleeding is present (often done by “urea clot lysis” method)
(e) More esoteric assays include PAI-1 activity and antiplasmin
Factor I / fibrinogen deficiency or disorders
Rare
Autosomal inheritance; most mutations are in alpha-fibrinogen chain gene, sparing beta and gamma chains
Often associated with bruising, epistaxis, menorrhagia, GI/GU bleeding, umbilical stump bleeding, miscarriage, poor wound healing; also bleeding after surgery, trauma, dental procedures, pregnancy or circumcision
May prolong PT and PTT
Need 100 mg/dL of fibrinogen for surgical hemostasis; biologic half life is 72-120 hours; less is needed in non-surgical conditions, if there is no severe hemostatic challenge
Afibrinogenemia: homozygous form; causes severe quantitative deficiency of fibrinogen and increased risk of bleeding; associated with intracranial hemorrhages
Hypofibrinogenemia: heterozygous form; mild/moderate reductions in fibrinogen; little/no bleeding
Dysfibrinogenemia: qualitative fibrinogen deficiency with production of dysfunctional fibrinogen; usually heterozygous; usually either no symptoms or mild bleeding; may paradoxically be associated with thrombosis, with or without bleeding; often prolonged thrombin time and reptilase time, PT and PTT
Acquired causes: DIC, liver dysfunction - more common than hereditary deficiencies
Treatment: 1 unit of cryoprecipitate per 7 kg as needed to keep fibrinogen above 100 mg/dL, if symptomatic; one unit raises fibrinogen by 10 mg/dL (approximately); one unit of fresh frozen plasma contains at least twice as much fibrinogen as one unit of cryoprecipitate, but in a much larger volume
Factor II (prothrombin) deficiency
Rare
Autosomal inheritance
Need 10-40% for surgical hemostasis; biologic half life is 48-120 hours
Severe deficiencies associated with intracranial hemorrhage
Acquired hypoprothrombinemia can be associated with lupus-like inhibitors
Treatment: recombinant factor VIIa, alternatively 10-20 ml fresh frozen plasma/kg, then 3 ml/kg every 12-24 hours as necessary; prothrombin complex concentrates may be used for serious bleeding
Also called labile factor deficiency
Rare
Autosomal inheritance
Need 10-30% for surgical hemostasis, biologic half life is 12-36 hours
May be associated with bruising, epistaxis, menorrhagia, GI/GU bleeding, umbilical stump bleeding or bleeding after surgery, trauma, dental procedures, pregnancy or circumcision
Severe deficiencies associated with intracranial hemorrhage, although levels don’t always correlate with severity of symptoms
Treatment: 10-20 ml fresh frozen plasma/kg, then 3-6 ml/kg every 12 hours as necessary; commercial concentrates of factor V are not available
Also called autoprothrombin I deficiency
Rare
Autosomal inheritance
Need 10-25% for surgical hemostasis, biologic half life is 4-7 hours
May be associated with bruising, epistaxis, menorrhagia, GI/GU bleeding, umbilical stump bleeding or bleeding after surgery, trauma, dental procedures, pregnancy or circumcision
Severe deficiencies may resemble hemophilia A or B, and are associated with intracranial hemorrhage
Levels don’t always correlate with severity of symptoms
Treatment: 10-20 ml fresh frozen plasma/kg, then 3-6 ml/kg every 4 hours as necessary
Factor VIII deficiency (Hemophilia A)
Most common severe hereditary bleeding disorder
X linked recessive disorder; (gene is on X chromosome)
Need 80-100% for surgical hemostasis with major surgery or major bleeding, 30-50% postoperatively or to prevent minor bleeding
Biologic half life is 8-12 hours
Affects 1 per 5-10K males; female carriers are usually unaffected unless they have imbalanced inactivation (lyonization), Turner’s syndrome or other rare X chromosomal abnormalities; females with disease are rare (daughters of affected male and carrier female)
Clinical severity varies with factor levels: >5%: bleeding only with surgery or trauma; 1-5%; moderate bleeding; <1%: severe disease with spontaneous bleeding
30% of cases arise from new mutations, so there may be no family history
Symptoms: bleeding into muscle, soft tissue or joints (hemarthrosis), GI/GU tract; easy bruising, excessive bleeding after surgery, trauma, dental procedures or circumcision; epistaxis, poor wound healing, post-traumatic intracranial hemorrhage
Laboratory: prolonged PTT and normal PT in males with unexplained bleeding; measure factor VIII and IX levels (values of 20-30% of normal may cause prolonged PTT) and von Willebrand test panel (reduced factor VIII may be due to decrease in vWF; in female hemophilia A carriers, factor VIII/vWF ratio is 0.5 vs. 1.0 in normal females)
Notes: (a) factor VIII and vWF may be elevated during acute phase reactions, including pregnancy; must repeat tests when acute phase reaction has subsided; (b) factor VIII is labile at room temperature, and mild/moderate decreases may be due to improper processing and storage
Molecular: 40% in Caucasians are due to inversion of intron 22; also numerous other mutations; gene is large; RFLP analysis may be useful in families without the intron 22 mutation
Treatment: factor VIII concentrates (now treated to destroy viruses, but HIV+ in early 1980’s); 1 unit/kg raises levels in vivo by 2%
major surgery/bleeding - 40-50 units factor VIII concentrate/kg every 12 hours as necessary, usually for 7-10 days,
postoperatively - 15-25 units/kg every 12 hours as necessary, usually for 7-10 days
minor bleeding - 15-20 units/kg every 12-24 hours as necessary for minor bleeding
mild/moderate bleeding - DDAVP (if patients respond to DDAVP)
References: Mol Pathol 2002;55:127 (molecular aspects)
Factor IX deficiency (hemophilia B)
Also called Christmas disease, autoprothrombin II deficiency
Severe hereditary bleeding disorder
X lined recessive disorder (gene is on X chromosome)
Need 50-80% of normal levels for surgical hemostasis with major surgery or major bleeding, 40% postoperatively, 30-50% to prevent minor bleeding
Affects 1 per 25-30K males; female carriers are unaffected; females with disease are rare
Clinical severity varies with factor levels: >5%: bleeding only with surgery or trauma; 1-5%; moderate bleeding; <1%: severe disease with spontaneous bleeding
Factor half life is 18-24 hours
Symptoms: bleeding into muscle, soft tissue or joints (hemarthrosis), GI/GU tract; easy bruising, excessive bleeding after surgery, trauma, dental procedures or circumcision; epistaxis, poor wound healing, post-traumatic intracranial hemorrhage
Laboratory: prolonged PTT and normal PT in males with unexplained bleeding; measure factor VIII and IX levels (values of 20-30% of normal may cause prolonged PTT) and von Willebrand test panel
Molecular: numerous mutations; genetic testing for female carriers or prenatal detection uses RFLP analysis
Treatment: factor IX concentrates (now treated to destroy viruses, but HIV+ in early 1980’s); 1 unit/kg raises levels in vivo by 1%
major surgery/bleeding - 50-80 units factor IX concentrate/kg every 12-24 hours as necessary, usually for 7-10 days
postoperatively - 40 units/kg every 12-24 hours, usually for 7 days
minor bleeding - postoperatively; 30-40 units/kg q 12-24 hours as necessary
Rare
Autosomal inheritance
Need 10-40% for surgical hemostasis, biologic half life is 24-48 hours
May be associated with bruising, epistaxis, menorrhagia, GI/GU bleeding, umbilical stump bleeding or bleeding after surgery, trauma, dental procedures, pregnancy or circumcision
Severe deficiencies may resemble hemophilia A or B, and are associated with intracranial hemorrhage
Treatment: 10-20 ml fresh frozen plasma/kg, then 3-6 ml/kg every 12 hours as necessary; may use prothrombin complex concentrates for serious bleeding
Common among Ashkenazi Jews
Autosomal inheritance
Need 15-50% for surgical hemostasis, biologic half life is 40-84 hours
May be associated with bruising, epistaxis, menorrhagia, GI/GU bleeding, umbilical stump bleeding or bleeding after surgery, trauma, dental procedures, pregnancy or circumcision
Levels don’t always correlate with severity of symptoms
Treatment: 10-20 ml fresh frozen plasma/kg, then 5-10 ml/kg every 24 hours as necessary
Note: factor XI concentrates may promote thromboembolic complications
Also called Hageman factor deficiency
Relatively common
Autosomal inheritance
Not needed in normal procoagulant pathways - deficiencies do not cause bleeding symptoms
May be implicated as cause of isolated, prolonged PTT after preanalytic variables and heparin contamination have been ruled out
Factor XII is activated by high molecular weight kininogen and prekallikrein
Activated factor XII converts prekallikrein to kallikrein, which activates more factor XII
Rare
Autosomal inheritance
Need 5-50% for surgical hemostasis, biologic half life is 9-12 days
Although fibrin clots form, they are weak and subsequently lyse
Normal PT and PTT
Patients commonly present with history of delayed bleeding; often associated with bruising, epistaxis, menorrhagia, GI/GU bleeding, umbilical stump bleeding, miscarriage, intracranial hemorrhage, poor wound healing; also bleeding after surgery, trauma, dental procedures, pregnancy or circumcision
Testing recommended if delayed bleeding, umbilical stump bleeding, or miscarriages (with normal PT and PTT)
Diagnosis: usually with “urea clot lysis” assay, although specific factor assay is available in specialized labs
50% of population has Val134Leu polymorphism, which may protect against deep venous thrombosis, but predispose to intracranial hemorrhage
Acquired causes of factor XIII deficiency: liver disease, DIC, Crohn’s disease, ulcerative colitis, Henoch-Schonlein purpura, leukemia, myelodysplasia, myeloproliferative disorders
Treatment: 500 ml plasma or 1 bag cryoprecipitate / 10 kg every 3 weeks
High molecular weight kininogen deficiency
Rare
Autosomal inheritance
Not needed in normal procoagulant pathways - deficiencies may cause marked prolongation of PTT, but do not cause bleeding symptoms
Rare