Table of contents :

• congenital coagulopathies
• hemorrhagic diathesis (deficiencies of pro-coagulatory factors)

Epidemiology : incidence = 1 every 5032 alive male newborns; prevalence = 13,4 cases per 100,000 males.
• factor XI deficit / hemophilia C / Rosenthal's disease

Epidemiology : identified by Rosenthal in 1953, common in Ashkenazi Jews
Aetiology : autosomal recessive mutations of factor XI
Symptoms & signs : hemorrhages after urogenital surgery
Laboratory examinations : enlengthened aPTT, normal bleeding time and INR, factor XI activity < 15% in homozygotes and 20-70% in heterozygotes
Therapy : replacement therapy with fresh frozen plasma. Some cases are responsive to desmopressin / 1-deamino-8-D-Arg vasopressin (DDAVP)
• factor IX / PTC deficiency / hemophilia B / Christmas' disease

Epidemiology : identified in 1952; prevalence = 15 every 1,000,000
Aetiology : 80 different recessive mutations of factor IX on Xq26-27, 30% arising de novo: homozygosity is lethal for embryos, so it can affect heterozygous females only if lyonization occurs in the wild-type gene)
• hemophilia B^- (50%) : absence of cross-reacting material (CRM)
• hemophilia B⁺ (30%) : presence of cross-reacting material (CRM)
• hemophilia B^M (15%) : enlengthened INR when using bovine thomboplastin; also Abs anti factor Xa
• hemophilia B Leiden : deficiency normalizes with puberty, since the promoter is still responsive to androgens
Pathogenesis : deficiency of factor IX
Clinical forms :
• mild : residual activity > 5 %
• moderate : 1 % < residual activity < 5 %
• severe : residual activity < 1%
Symptoms & signs : hemarthrus => ankylosing arthropathy; intramuscular, subperiosteal and subcutaneous hematomas; mucosal and cerebral hemorrhages => anemia
Laboratory examinations :  enlengthened aPTT, normal bleeding time and INR
Therapy :
• replacement therapy : fresh frozen plasma (factor IX resists low temperatures) => prothrombin complex concentrates (also factors VII and X; thrombotic complications) => rHuFIX. Only 50% of administered factor IX is recovered in plasma. Acquired inhibitors occur in 3-5% of patients and may cause severe anaphylactic reactions if the drug is not discontinued.

clinical manifestations	factor IX activity	rFIX
prophylaxis (to prevent hemophilic arthropathy)	< 15%	3-50 U/kg/day
mild hemorrhages (initial hemarthrus, mild hematomas, hematuria)	15-20%	15-20 U/kg/day
severe hemorrhages (hemarthrus, large painful hematomas, head trauma, gastrointestinal hemorrhages, minor surgery)	30-40%	30-40 U/kg/day
life-threatening hemorrhages (major trauma or surgery, intracranial hemorrhage)	60-80%	60-80 U/kg/day
dental extractions	> 30%	> 30 U/kg/day

• gene therapy
Prognosis : life expectancy = 49 years (mortality = transfusion-related HIV (41%) and hemorrhages (15%))
• factor VIII deficiency / hemophilia A / classical or true hemophilia
• Heckathorn's disease : a rare variant of hemophilia A in which the levels of coagulation factor VIII fluctuate
Epidemiology : 1:5000 males (45 per 1,000,000)
Aetiology : X-linked recessive mutations in factor VIII (positive anamnesis in 70%)
• rearrangements => severe hemophilia (partial inversion of intron 22 (40%) or intron 1 (3-5%), intragenic deletions > 100 bp, insertion of retrotransposons, duplications)
• nonsense mutations, insertions, deletioons < 100 bp => mild or intermediate hemophilia, with eventual cross-reacting material (CRM+) (5%), which usually do not develop acquired inhibitors after replacement therapy
Pathogenesis : insufficient generation of factor Xa, which is rapidly inactivated by TFPI
Differential diagnosis :
• vWD subtype 2N. (reduced factor VIII and normal bleeding time)
• combined factor V and VIII deficiency
• combined factor VII and VIII deficiency
Symptoms & signs :
• severe (50%) : factor VIII activity < 1% => frequent severe spontaneous (more episodes per week) hemarthrus (the subsynovial venous plexus is poor of tissue factor and rich in TFPI) => inflammation => neovascularization and subchondral bone cysts => increased subsceptibility to hemarthrus (knee > tibio-tarsal > elbow > wrist > shoulder > hip) => ankylosing arthropathy, muscle hematomas, subperiosteal, mucosal (epistaxis, hemophtoe), organ, and soft tissue bleedings within age 1 (2-10% cerebral bleedings at birth, even with caesarean delivery), often discovered after minor dental or tonsil surgery, 1 site
• intermediate (30% : factor VIII activity = 1-5% => rare spontaneous hemorrhages (< 3-5 hemarhruses per year), minor posttraumatic bleeding
• mild (20%) : factor VII activity 5-40% => bleeding only after severe trauma or surgery in adolescence
Laboratory examinations : increased aPTT, normal INR and bleeding time, posthemorrhagic hypochromic sideropenic anemia; PCR on chorial villi biopsy (week 9-12 of pregnancy) or umbilical blood (week 18-21 of pregnancy)
Therapy :
• replacement therapy (2% increase in activity for each unit/kg administered; 1% in babies < 20-30 kg; administered bid since half-life is 12 hrs)

clinical manifestations	factor VIII activity	rFVIII
prophylaxis (to prevent hemophilic arthropathy)	< 20%	3-50 U/kg 3 times a week for >= 1 month
mild hemorrhages (initial hemarthrus, mild hematomas, hematuria)	20-30%	10-15 U/kg/bid
severe hemorrhages (hemarthrus, large painful hematomas, head trauma, gastrointestinal hemorrhages, minor surgery)	40-50%	20-25 U/kg/bid
life-threatening hemorrhages (major trauma or surgery, intracranial hemorrhage)	80-100%	40-50 U/kg/bid
dental extractions	30%	> 15 U/kg/bid

It costs > $100 000 per year for patients with less than 1% of normal activity. A feared complication of human fVIII replacement therapy is the development of inhibitors, which occurs in 10-25% of patients with severe disease^ref. Inhibitors can be eradicated in 70% of patients with immune tolerance induction, which involves frequent injections of high doses of human fVIII and costs $1 000 000 per year for a child. Although patients with inhibitors are treated effectively with bypass agents such as recombinant factor VIIa, one dose of fVIIa for a 53-kg patient costs $10 464 at our hospital. Total costs for 7 to 10 days of treatment after major surgery or a serious bleed can exceed $500 000. Presurgical treatment consists of plasmapheresis for 2 days or administration of some Bethesda units to saturate neutralizing autoAbs.
• low responders : titre < 10 BU
• high responders : titre > 10 BU
rHuFVIII : 90 mg/kg every 3-4 hours (half-life = 2-3 hours). Tolerance-induction therapy with FVIII (50-200 U/kg/day or 2-3 times a week) eradicates inhibitors in 40%.
• desmopressin / 1-deamino-8-D-Arg vasopressin (DDAVP) 0.3 mg/kg in NS i.v. infusion (10-30 minutes) or s.c. or i.n. bid for mild hemophilia, associated with antifibrinolytic drugs (it induces release of PAI, too) such as tranexamic acid p.o./i.v. (not in microhematuria due to risk of urothrombosis)
• GR agonists in acute hemarthrus arthropathy
• gene therapy
Prognosis : life expectancy = 49 years (mortality = transfusion-related HIV (41%) and hemorrhages (15%))
• vWF deficiency / von Willebrand disease (vWD) / hereditary pseudohemophilia / vascular hemophilia / angiohemophilia

Epidemiology : prevalence = 1-2% in the general population (100 per million), according to screening studies. In contrast, estimates based on referral for symptoms of bleeding suggest a prevalence of 30 to 100 cases per million, which is similar to the prevalence of hemophilia A. The disease was first described in 1926 by the Finnish pediatrician Erik von Willebrand, who used a rowboat to make house calls to patients with the disease in the Åland archipelago.
Aetiology : autosomal dominant mutations in von Willebrand's factor on chromosome 12
• type 1 (70%; autosomal dominant with variable penetrance) : down-regulation of expression => partial quantitative and qualitative deficiency, reduced ristocetin-induced platelet aggregation (RIPA)
• type 2 acquired von Willebrand's disease / von Willebrand's syndrome (15-20%) : mutations in cds => qualitative alterations
• subtype 2A (< 10%; autosomal dominant > recessive) : no HMWMs formation due to any mutation within the A2 domain of vWF on chromosome 12 that make the A domain(s) more susceptible to shear-induced conformational change and increase the susceptibility to proteolysis by ADAMTS13^ref
• group 1 mutations impair the secretion of VWF into plasma
• group 2 mutations represents those that enhance proteolysis by ADAMTS13
• subtype 2B (5%) : increased ristocetin-induced platelet aggregation (RIPA), sometimes associated to thrombocytopenia
Location of mutations in types IIa and IIb vWD. Mutations in the region of the protein between amino acids 742 and 875 have been identified in patients with type IIa disease. These result in a deficiency in high- and medium-molecular-weight multimers due either to failure to secrete high-molecular-weight forms of vWF or to their proteolytic degradation in the circulation. In type IIb disease, there is also a decrease in high-molecular-weight vWF, but the defect is due to the failure of vWF with mutations in the A-1 domain of the protein (amino acids 509-695) to bind properly to platelet glycoprotein Ib/IX.

• subtype 2M or Vicenza variant (rare, autosomal dominant) : decreased binding with gpIb
• subtype 2N or Normandy variant (rare; autosomal recessive) : decreased binding with factor VIII. Differential diagnosis with hemophilia A.
Aetiology : severe calcific aortic stenosis (AS)
Symptoms & signs : slatentization of intestinal angiodysplasia (IA)
Therapy : aortic valve replacement
• type 3 : total quantitative deficiency => no ristocetin-induced platelet aggregation (RIPA)
• platelet-type vWD or pseudo-vWD : deficiency of gpIb, the receptor for vWF
Pathogenesis : reduction of circulating factor VIII
Symptoms & signs : type 1 < type 2 < type 3
• [ ] < 50% : no symptoms
• [ ] < 30% : symptomatology occurs : prolonged bleeding time and often impairment of adhesion of platelets on glass beads. Mostly mucosal hemorrhages (very rarely hemarthrus)
• epistaxis (65-70%)
• after dental extraction (50-55%)
• gingival bleeding (30-45%)
• menorrhage (15-40%)
• ecchymoses and hematomas (15-40%)
• post-traumatic bleeding (15-40%)
• after surgery (10-25%)
• gastrointestinal hemorrhages (8-12%)
• tonsillar hemorrhage (3-8%)
• hemarthus (3-8%)
• other locations (3-5%)
Laboratory examination : prolonged bleeding time (rarely normal) and prolonged aPTT
• wWF:RCo test measures the interaction of vWF with GPIb
• FVII:C
• vWF:Ag
• ristocetin-induced platelet aggregation (RIPA)
Therapy :
• replacement therapy : 40-60 IU FVIII/kg improves vWF:Ag and vWF:RCo for 6-8 hours => bid
• desmopressin / 1-deamino-8-D-Arg vasopressin (DDAVP) 0.3 mg/kg i.v. infusion (15-30 minutes) or s.c. bid reduces surgical risk by inducing release of more vWF from endothelial Weibel-Palade bodies (3-5 fold increase). It is indicated for type 1, 2M, 2N and some 2A vWD, while in type 2B may worsen thrombocytopenia
• Because the cDNA for von Willebrand factor (VWF) is 8.4 kb, the potential for gene therapy using common viral vector delivery has been considered problematic. Type 3 or homozygous severe von Willebrand disease (VWD) is relatively rare and is estimated to affect 3 to 4 individuals per million^ref. Although transfection of canine type 3 VWD endothelial cells has been reported previously^ref in Blood, such transfection was done only with cultured endothelial cells using a plasmid containing the cDNA for VWF under the control of the cytomegalovirus (CMV) promoter. It would be difficult to procure a source of such endothelial cells in a practical manner that could be a potential strategy for in vivo gene transfer. Hebbel and coworkers^ref have previously defined a mechanism for procuring circulating endothelial cells or endothelial progenitor cells from blood that permit the ex vivo expansion of endothelial cells that could be the target for gene delivery and potential subsequent re-introduction into the recipient. This had been achieved using human blood but had not been achieved in another species^ref. Delivery of the VWF cDNA using a retroviral vector has the potential for long-term expression of VWF synthesis, but the 8.4-kb cDNA has been thought to be a barrier to efficient viral gene transfer. DeMeyer and colleagues have been able to demonstrate efficient and effective gene transfer using a lentiviral packaging system in which VWF expression is under the control of the CMV promoter. Not only do they demonstrate that model endothelial cells can be isolated from peripheral blood of type 3 VWD dogs and that VWF synthesis can be transferred by lentiviral transduction, but the VWF that synthesized is fully multimerized and binds factor VIII (FVIII), binds to platelet glycoprotein Ib (GPIb) under expected agonist induction using ristocetin, and binds normally to collagen. Furthermore, the endothelial cells reestablish their Weibel-Palade body storage of VWF as demonstrated. Furthermore, not only can the cDNA for VWF using the CMV promoter be packaged in a lentiviral vector, but the titer of virus and the efficiency of cellular transduction suggests this is a viable approach. This now provides an opportunity to study ex vivo gene transfer for the treatment of type 3 VWD. Whether ex vivo expansion and in vivo homing would provide therapeutic in vivo VWF levels will require additional study. Infusion of VWF in this canine VWD model has been previously demonstrated to be therapeutic^ref. One observation by DeMeyer et al that could be a potential barrier to future success is the demonstrated decline in transgene expression and proliferative potential after long-term expansion. The authors point out that this phenomenon seems to be more of a problem with canine outgrowth endothelial cells than with human. It is not clear if this will be a stumbling block to long-term correction in vivo or whether the homing of these cells will be established in an environment that will permit long-term genetic correction. There are several questions that will await further study. Optimally, does VWF need to be expressed in the endothelial cells lining our blood vessels, or is the provision of multimerized VWF to the plasma compartment from transduced cells sufficient? Is platelet expression of VWF important to optimal therapeutic benefit? The canine model of VWF synthesis varies from other species in that VWF synthesis and storage is limited to endothelial cells and does not occur in megakaryocytes (and their platelet progeny). Thus, correcting the endothelial compartment will normalize dogs, because they do not use platelets for VWF storage and release. In other animals, including humans, VWF has both endothelial and megakaryocytic synthesis and storage. Since VWF infusion alone is therapeutically beneficial in humans, the source of cellular released VWF may be more dependent on the quantity and quality of the VWF secreted into plasma. Blood-outgrowth endothelial-cell VWF appears to meet the need for quality of VWF, but whether adequate quantity will be achieved in vivo will only be answered by further study^ref
• factor VII deficiency / Alexander's disease

Aetiology : autosomal recessive mutations of factor VII with variable penetrance
• hypoproconvertinemia (80%)
• dysproconvertinemia (20%)
Symptoms & signs : mucosal and posttraumatic hemorrhages, severe when activity < 2%
Laboratory examinations : prolonged INR (use different thromboplastins) and normal aPTT
Differential diagnosis : liver disease, vitamin K deficiency, congenital jaundice and homocystinuria
Therapy : replacement therapy during hemorrhages with daily i.v. infusions of fresh frozen plasma or factor VII concentrate. Vitamin K is not effective
• factor X deficiency or Telfer's disease

Aetiology : mutations of factor X
Laboratory examinations : prolonged INR and normal aPTT
• factor V deficiciency or Owren's parahemophilia

Aetiology : autosomal recessive mutations of factor V, reducing activity to 1-10%
Symptoms & signs : mucosal and posttraumatic hemorrhages, rarely hemarthrus and deep hematomas
Laboratory examinations : prolonged bleeding time, INR, and aPTT
Differential diagnosis : combined factor V and VIII deficiency
Therapy : replacement therapy with fresh frozen plasma
• factor II / prothrombin deficiency (11%)
• congenital hypoprothrombinemia
• congenital dysprothrombinemia
Aetiology : autosomal recessive mutations in the catalytic or factor-X-binding domains of factor II
Symptoms & signs : mucosal and posttraumatic hemorrhages
Laboratory examinations : prolonged INR, aPTT and dosage of factor II
Therapy : replacement therapy with fresh frozen plasma => prothrombin complex until factor II activity > 10% (ideally 50%). Vitamin K is not effective
• factor I / fibrinogen deficiency

Aetiology : mutations of factor I
• congenital afibrinogenemia

Epidemiology : identified by Rabe and Sallmon in 1920; prevalence = 1 every million
Aetiology : autosomal recessive mutations with variable penetrance
Symptoms & signs : severe hemorrhages, relapsing abortion in first trimester, disabling hemarthrus (20%), improving with age
Laboratory examinations : prolonged bleeding time and no coagulation in any test
Differential diagnosis : hyperfibrinolysis
Therapy : replacement therapy until fibrinogenemia > 100 mg/dl; estroprogestin contraceptives to prevent menorrhages
• congenital hypofibrinogenemia

Aetiology : autosomal dominant (hereterozygous afibrinogenemia ??)
Laboratory examinations : fibrinogenemia < 50 mg/dl
• congenital dysfibrinogenemia

Aetiology : hundreds of autosomal dominant mutations impairing fibrinogen releaase, polymerization of stabilization
Symptoms & signs : asymptomatic, hemorrhages or thromboses,
Laboratory examinations : prolonged INR, aPTT, TT and reptilase time; reduced factor XII and hyperfibrinolysis in some variants
• factor XIII deficiency
• type I : both a and b subunits
• type II : only a subunit is deficient
• type III : only b subunit is deficient
Aetiology : autosomal recessive mutations of factor XIII
Symptoms & signs : hemorrhages since umbilical stump detachment, intracranial hemorrhages
Laboratory examinations : normal bleeding time, INR and aPTT; dosage of factor XIII (coaguli are soluble in organic solvents (urea 5 M or chloroacetic acid 1%))
Therapy : replacement thearpy with fresh frozen plasma, cryoprecipitate, or concentrates until activity > 3% => administered every 3 weeks for prophylaxis of cerebral hemorrhages
• vitamin K deficiency bleeding (previously called hemorrhagic disease of the newborn (HDN)) : a self-limited hemorrhagic disorder of the first days of life
Aetiology : deficiency of the vitamin K-dependent blood coagulation factors II, VII, IX, and X

• newborns
  
• bile acid malabsorption and those taking cholestyramine, deficiency of other fat soluble vitamins (K, A, D, and E) ^ref
  

Laboratory examinations : severe deficiency of clotting factor II (2%; normal 50–200%), factor VII(3%; 50–200%), factor IX (6%; 50–200%), and factor X (1%; 50–200%), with preserved clotting factors V, VIII, XI, and XII. Protein Induced by Vitamin K Absence II (PIVKA-II)
Therapy : Vitamin K prophylaxis for neonates, recommended since the 1960s, is supported by a Cochrane review. The UK national programme of vitamin K replacement at birth is associated with a decrease in the incidence of vitamin K deficiency bleeding, most importantly intracranial haemorrhage^{ref1, ref2}, with associated improvements in perinatal mortality, and short-term and long-term morbidities (1.2 to 1.8 per 100 000 births).

• combined deficiencies
• combined factor V deficiency and factor VIII deficiency
• combined factor VII deficiency and factor VIII deficiency
Symptoms & signs : hemorrhages and hemophilic pseudotumors
The World Hemophilia Day is on April 17 each year.
Web resources :
• World Federation of Hemophilia (WFH)
• National Hemophilia Foundation (NHF) of USA
• non-hemorrhagiparous coagulopathies (deficiencies of unessential pro-coagulatory factors)
• prekallikrein B / plasma kallikrein / Fletcher factor deficiency

Aetiology : autosomal recessive mutations
Laboratory examinations : prolonged aPTT, normal INR, dosage of prekallikrein
• HMWK / Flaujeac factor deficiency

Aetiology : autosomal recessive mutations
Laboratory examinations : prolonged aPTT, normal INR, dosage of HMWK
• thrombophilic coagulopathies (deficiencies of anti-coagulatory factors)
• factor XII deficit of Hageman trait or Ratnoff's disease

Epidemiology : identified by Ratnoff in 1955
Aetiology : autosomal recessive mutations of factor XII
Symptoms & signs : as factor XII also activates fibrinolysis, main symptoms are thrombotic instead of hemorrhagic. This shows that in vivo only the extrinsic pathway of coagulation, triggered by tissue factor, works
Laboratory examinations : prolonged aPTT, normal INR
Therapy : none required
• congenital dysfibrinogenemia
• thrombin hyperactivity / prothrombin G20210A

Epidemiology : prevalence = 2%
Aetiology : autosomal dominant mutations of thrombin
Symptoms & signs : RR = 3 for DVT. The annual incidence of a first VTE was 0.37% (95%CI: 0.08-1.08) for carriers and 0.12% (95%CI 0.00-0.69) for non-carriers (HR 3.1; 95%CI 0.3-29.6). The annual incidence of a first arterial cardiovascular event was 0.56% (95%CI 0.18-1.31) for carriers and 0.73% (95%CI 0.27-1.58) for non-carriers (adjusted HR 0.7, 95% CI 0.2-2.5). The absolute incidence of a first VTE or arterial cardiovascular event is low; therefore, the clinical implications of carriership of the prothrombin 20210A mutation are limited and routinely testing all first degree relatives of probands with this mutation does not appear to be justified^ref.
Laboratory examinations : thrombin activity = 130%
• antithrombin III / heparin cofactor I deficiency

Epidemiology : prevalence = 0.02%
Aetiology : mutations of antithrombin III
• type I : expression down-regulation
• type II : mutations in cds
• reactive site (RS)
• heparin-binding site (HBS) (the least severe)
• pleiotropic effects (PE)
Symptoms & signs : the highest risk for DVT
Differential diagnosis : acquired deficiency
Therapy : replacement therapy
• CD141 / thrombomodulin deficiency

Aetiology : mutations of thrombomodulin
• protein C deficiency

Epidemiology : prevalence = 0.2-0.4%
• type I : neither Ag reactivity nor functionality
• type II : Ag reactivity with no functionality
Aetiology : mutations of protein C
Symptoms & signs : asymptomatic or, if < 5%, => purpura fulminans (DIC), skin necrosis when starting oral anticoagulants
Pathogenesis : the anticoagulant, activated Protein C (aPC), possesses antithrombotic, profibrinolytic, antiinflammatory, and antiapoptotic properties, and the level of this protein is an important marker of acute inflammatory responses. While infusion of aPC improves survival in a subset of patients with severe sepsis, evidence as to how aPC decreases mortality in these cases is limited. Since a total deficiency of PC shows complete neonatal lethality, no animal model currently exists to address the mechanistic relationships between very low endogenous aPC levels and inflammatory diseases. Novel genetic dosing of PC strongly correlates with survival outcomes following LPS challenge in mice. The data provide evidence that very low endogenous levels of PC predispose mice to early onset disseminated intravascular coagulation, thrombocytopenia, hypotension, organ damage, and reduced survival after LPS challenge. Furthermore, evidence of an exacerbated inflammatory response is observed in very low-PC mice, but is greatly reduced in WT cohorts. Reconstitution of low-PC mice with recombinant human aPC improves hypotension and extends survival after LPS challenge. This study directly links host endogenous levels of PC with various coagulation, inflammation, and hemodynamic endpoints following a severe acute inflammatory challenge^ref.
Laboratory examinations : proteins induced by vitamin K absence (PIVKA)
• protein S deficiency

Epidemiology : prevalence = unknown
Aetiology : mutations of protein S
• type I : neither Ag reactivity nor functionality
• type II : Ag reactivity with no functionality
• type III : increased total protein, decreased free protein
Laboratory examinations : quantification of free protein S
Differential diagnosis : factor V Leiden
• plasminogen deficiency

Epidemiology : prevalence = unknown
Aetiology : autosomal doinant mutations of plasminogen
• type I : neither Ag reactivity nor functionality
• type II : Ag reactivity with no functionality
Therapy : thrombolytic and fibrinolytic drugs
• heparin cofactor II deficiency

Aetiology : autosomal dominant mutations of heparin cofactor II
• u-PA deficiency

Aetiology : mutations of u-PA
• PAI excess

Aetiology : mutations of PAI
• resistance to activated protein C (APC)
• factor V Leiden (85-90%)

Epidemiology : prevalence = 2.5%; 5% of Caucasians, but rarely found among black people
Aetiology : autosomal dominant G1691A => Arg506Gln (R506Q) mutation of factor V
Symptoms & signs : 5-7-fold risk of DVT (90-fold in homozygotes) and a 10-fold risk if the carrier is taking oral contraceptives => miscarriages
Laboratory examinations : aPTT measured before and after addition of APC
• hyperhomocysteinemia-induced hereditary thrombophilia

Epidemiology : prevalence = 5%
Aetiology :
• autosomal dominant mutations in cystathionine-b-synthase (prevalence = 0.3-1.4%)
• autosomal recessive mutations in 5,10-methylene-tetrahydrofolate reductase (prevalence = 5%)
Pathogenesis, Symptoms & signs, Laboratory examinations, and Therapy  : see hyperhomocysteinemia
• elevated factor VIII (activity > 150%)

Epidemiology : prevalence = 11%
• membrane endothelial protein C receptor (mEPCR) heterozygosity results in a mild increase of thrombosis tendency and little influence on the response to endotoxin. Physiologically elevated soluble EPCR (sEPCR) do not regulate protein C activation^ref
Symptoms & signs : arterial thromboses and venous thromboses
• episode before age 60 without apparent cause
• first episode of DVT before age 45
• at least 1 other relative with DVT or PE before age 60 without apparent cause
• relapse of DVT or PE
• thrombosis in mesenteric veins, porta vein, or cerebral veins
• frequent superficial venous thromboses without neoplasia
• acquired coagulopathies^ref
• acquired hemorrhagic coagulopathies
• defective synthesis of coagulation factors

Aetiology :
• chronic hepatopathies (reduced synthesis of factors II, VII, IX and X, antithrombin, protein C and S, plasminogen, PAI, protein Z, thrombocytopenia and alterations of microcirculation, reduced clearance of activated coagulation factors)
• vitamin K deficiency :
• reduced intake : poor feeding, protein or carbohydrate diets, elderlies or inanition
• intestinal malabsorption : celiac disease, gastro- and enterectomy, cholecystocholic fistulas, deficiency of pancreatic lipase in pancreatitis, obstructive jaundice with deficient biligenesi, portal hypertension, malnutrition in chronic alcoholism
• biliary ways obstruction : intra- and extrahepatic, total or partial
• alterations of intestinal flora : in hemorrhagic disease of newborn, expecially if immature
Laboratory examinations : proteins induced by vitamin K absence (PIVKA)
• increased intravascular consumption (consumptive thrombohaemorrhagic disorders)
• postvaricella purpura fulminans is a rare disease in children that is probably caused by an acquired protein S deficiency resulting from antiprotein S antibodies after HHV-3 / VZV infection. The epitope of these antibodies are situated on both the first 242 amino acids of protein S and the sex hormone binding globulin-like domain.
• disseminated intravascular coagulopathy (DIC) / intravascular coagulation-fibrinolysis (ICF)

Aetiology :
• acute/subacute DIC :
• infections :
• LPS : Waterhause-Friderichsen syndrome, Shwartzman-Sanarelli reaction, ...
• HHV-3 / VZV
• obstetric complications :
• abruptio placentae (50% of all patients)
• amniotic fluid embolism (AFE) / anaphylactoid syndrome of pregnancy
• sepsis (30-40% of all patients)
• therapeutic abortion
• uterine rupture
• hydatiform mole
• hematological neoplasia
• acute promyelocytic leukemia (10% of all leukemia patients)
• advanced leukemic lymphoma
• large tissue damage
• burns
• hyperthermia
• cerebral trauma
• crushing injury
• rhabdomyolysis
• Hymenoptera bites
• snake venoms
• chronic DIC :
• solid metastatic neoplasms (10% of all patients)
• obstetric complications
• retention of dead fetus
• gravidic toxemia
• localized intravascular coagulation
• aortic aneurysm
• cavernous hemangioma
• liver diseases
• Le Veen shunt
• fulminating hepatitis
• hemolytic uremic syndrome (HUS)
• preeclampsia
• autoimmune disease
• SLE
• catastrophic antiphospholipid syndrome (APS)
Pathogenesis : excess of tissue factor in peripheral blood and systemic inflammation (IL-1, IL-6, and TNF-a) => uncontrolled generation of thrombin => massive systemic intravascular activation of coagulation, leading to =>
• widespread deposition of fibrin in the circulation which can compromise the blood supply to various organs, thus contributing to multiple organ failure
• consumption of platelets and coagulation proteins resulting from the ongoing coagulation => severe bleeding^{ref1, ref2, ref3, ref4, ref5, ref6}.
However, DIC is not a disease itself but is always secondary to an underlying disorder^{ref1, ref2}. In fact, a variety of clinical conditions may cause systemic activation of coagulation. Table 1 lists the diseases most frequently associated with DIC. Bacterial infections, in particular septicemia, are the most common clinical conditions associated with DIC. There is no difference in the incidence of DIC in patients with Gram-negative or Gram-positive sepsis. Systemic infections by other micro-organisms, such as viruses and parasites, may also lead to DIC. The generalized activation of coagulation occurring in these cases is mediated by cell membrane components of micro-organisms (lipopolysaccharide or endotoxin) or bacterial exotoxins, such as staphylococcal b hemolysin, which cause a generalized inflammatory response through the activation of pro-inflammatory cytokines^{ref1, ref2, ref3, ref4, ref5}. Severe trauma and burns are other conditions frequently associated with DIC^{ref1, ref2}. Both solid and hematologic cancers may be associated with DIC, which can complicate up to 15% of cases of metastasized tumors or acute leukemia^{ref1, ref2, ref3}. DIC is also a frequent complication (occurring in > 50% of cases) of some obstetric conditions such as abruptio placentae and amniotic fluid embolism^{ref1, ref2}. Finally, selected vascular disorders, such as giant hemangiomas and large aortic aneurysms, and severe toxic or immunological reactions (snake bites, drugs, hemolytic transfusion reactions and transplant rejection) can be associated with DIC^{ref1, ref2}.

Most of the recent advances in our understanding ofthe pathogenesis of DIC are derived from studies in animal models and humans with severe sepsis^ref. These studies have demonstrated that the systemic formation of fibrin observed in this setting is the result of the simultaneous coexistence of 4 different mechanisms: increased thrombin generation, a suppression of the physiologic anticoagulant pathways, impaired fibrinolysis and activation of the inflammatory pathway^{ref1, ref2, ref3}. The systemic generation of thrombin has been shown to be mediated predominantlyby the extrinsic (factor VIIa) pathway. In fact, while the abrogation of the tissue factor/factor VIIa pathway resulted in complete inhibition of thrombin generation in experimental animal models of endotoxemia, the inhibition of the contact system did not prevent systemic activation of coagulation^{ref1, ref2}. Impaired function of physiological anticoagulant pathways may amplify thrombin generation and contribute to fibrin formation^ref. Plasma levels of antithrombin are markedly reduced in septic patients as a result of a combination of increased consumption by the ongoing formation of thrombin, enzyme degradation by elastase released from activated neutrophils, impaired synthesis due to liver failure and vascular capillary leakage^{ref1, ref2, ref3}. Likewise, there may be significant depression of the protein C system, caused by enhanced consumption, impaired liver synthesis, vascular leakage and a down-regulation of thrombomodulin expression on endothelial cells by pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-? and interleukin(IL)-1?^{ref1, ref2, ref3}. Moreover, the evidence that administration of rTFPI results in complete inhibition of endotoxin-induced thrombin generation suggests that tissue factor is involved in the pathogenesis of DIC^{ref1, ref2}. Although no acquired or deficiency or functional defect of TFPI has been identified in patients with DIC, there is evidence that the inhibitor does not regulate tissue factor activity sufficiently in such patients^ref. As regards impaired fibrinolysis, experimental models of bacteremia and endotoxemia are characterized by rapidly increasing fibrinolytic activity, most probably due to the release of plasminogen activators from endothelial cells. However, this initialhyperfibrinolytic response is followed by an equally rapid suppression of fibrinolytic activity, due to the increase in plasma levels of plasminogen activator inhibitor type 1 (PAI-1)^{ref1, ref2} [Levi M, van der Poll T, de Jonge E, ten Cate H: Relative insufficiency of fibrinolysis in disseminated intravascular coagulation. Sepsis 2000, 3:103-109]. The importance of PAI-1 in the pathogenesis of DIC is further demonstrated by the fact that a functional mutation in the PAI-1 gene, the 4G/5G polymorphism, which causes increased plasma levels of PAI-1, was linked to a worse clinical outcome in patients with meningococcal septicemia^ref. Finally, another important mechanism in the pathogenesis of DIC is the parallel and concomitant activation of the inflammatory cascade mediated by activated coagulation proteins, which in turn can stimulate endothelial cells to synthesize pro-inflammatory cytokines. In fact, while cytokines and inflammatory mediators can induce coagulation, thrombin and other serine proteasesinteract with protease-activated receptors on cell surfaces to promote further activation and additional inflammation^ref. Furthermore, since activated protein C has an anti-inflammatory effect through its inhibition of endotoxin-induced production of TNF-?, IL-1?, IL-6 and IL-8 by cultured monocytes/macrophages, depression of the protein C system may result in a pro-inflammatory state^ref. Thus, inflammatory and coagulation pathways interact with each other in a vicious circle which amplifies the response further and leads to dysregulated activation of systemic coagulation (van der Poll T, Buller HR, ten Cate H: Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Eng J Med 1990, 322:1622-1627). Table 2 summarizes the most important mechanisms in the pathogenesis of DIC in sepsis. However, there is evidence that various events, including the release of tissue material (fat, phospholipids, cellular enzymes) into the circulation, hemolysis and endothelial damage may promote the systemic activation of coagulation in severe trauma and burns through a mechanism similar to that observed in septic patients (i.e., systemic activation of cytokines)^{ref1, ref2}. Nevertheless, there may also be specific variations in the pathogenesis if DIC due to different underlying disorders. For example, in some patients with cancer the initiation of coagulation activation is not only due to tissue factor expression on the surface of the malignant cells but in this case also involves a specific cancer procoagulant, a cysteine protease with factor X activating properties^ref. Patients with acute promyelocytic leukemia have a peculiar form of DIC characterized by a severe hyperfibrinolytic state associated with systemic activation of coagulation^ref.

The most common clinical manifestations of DIC are bleeding, thrombosis or both, often resulting in dysfunction of one or more organs^ref [Bick RL: Disseminated intravascular coagulation: objective clinical and laboratory diagnosis, treatment and assessment of therapeutic response. Semin Thromb Haemost 1996, 22:69-88]. A schematic representation of the clinical manifestations of coagulation abnormalities in DIC is presented in Figure 1. Since no single laboratory test or set of tests is sensitive or specific enough to allow a definite diagnosis of DIC, in most cases the diagnosis is based on the combination of results of laboratory investigations in a patient with a clinical condition known to be associated with DIC^{ref1, ref2}. The classical characteristic laboratory findings include prolonged clotting times (prothrombin time, activated partial thromboplastin time, thrombin time), increased levels of fibrin-related markers (fibrin degradation products [FDP], D-dimers), low platelet count and fibrinogen levels and low plasma levels of coagulation factors (such as factors V and VII) and coagulation inhibitors (such as antithrombin and protein C)^{ref1, ref2}. However, the sensitivity of plasma fibrinogen levels for the diagnosis of DIC is low, since fibrinogen acts as an acute-phase reactant and its levels are often within the normal range for a long period of time. Thus, hypofibrinogenemia is frequently detected only in very severe cases of DIC^{ref1, ref2}. On the other hand, FDP and D-dimer levels have a low specificity since many other conditions, such as trauma, recent surgery, inflammation or venous thromboembolism, are associated with elevated levels of these fibrin-related markers. Other, more specialized and useful tests, not available in all laboratories, include the measurement of soluble fibrin and assays of thrombin generation, such as those to detect prothrombin activation fragments F1+2 or thrombin-antithrombin complexes^{ref1, ref2}. However, serial coagulation tests may bemore helpful than single laboratory results in establishing the diagnosis of DIC. A scoring system for the diagnosis of DIC, developed from a previously described set of diagnostic criteria^ref, has been proposed by the Scientific Subcommittee on DIC of the International Society on Thrombosis and Haemostasis (ISTH)^{ref1, ref2}. This system consists of a 5-step diagnostic algorithm, in which a specific score, reflecting the severity of the abnormality found, is given to each of the following laboratory tests: platelet count (>100 × 10⁹/L = 0; <100 × 10⁹/L = 1, <50 × 10⁹/L = 2), elevated fibrin-related markers (e.g. soluble fibrin monomers/fibrin degradation products) (no increase = 0; moderate increase = 2; strong increase = 3), prolonged prothrombin time (< 3 sec. = 0; > 3 sec. but < 6 sec. = 1; > 6 sec. = 2), fibrinogen level (> 1 g/L = 0; < 1 g/L = 1). A total score of 5 or more is considered to be compatible with DIC. According to recent observations, the sensitivity and specificity of this scoring system are high (more than 90%)^ref. However, an essential condition for the use of this algorithm is the presence of an underlying disorder known to be associated with DIC^ref. Finally, a scoring system for diagnosing non-overt DIC has recently been proposed by the ISTH Scientific Subcommittee and validated by Toh and Downey who demonstrated its feasibility and prognostic relevance^ref.
Treatment of DIC : the heterogeneity of the underlying disorders and of the clinical presentations makes the therapeutic approach to DIC particularly difficult^{ref1, ref2}. Thus, the management of DIC is based on the treatment of the underlying disease, supportive and replacement therapies and the control of coagulation mechanisms. The recent understanding of important pathogenetic mechanisms that may lead to DIC has resulted in novel preventive and therapeutic approaches to patients with DIC^ref. However, in spite of this progress, the therapeutic decisions are still controversial and should be individualized on the basis of the nature of DIC and the severity of the clinical symptoms^{ref1, ref2} [Riewald M, Riess H: Treatment options for clinically recognized disseminated intravascular coagulation. Semin Thromb Haemost 1998, 24:53-59]. The treatment for DIC include replacement therapy, anticoagulants, restoration of anticoagulant pathways and other agents^{ref1, ref2, ref3}. Most of the clinical studies reported in the next paragraphs were conducted in patients with severe sepsis^{ref1, ref2}, a condition which usually leads to generalized activation of coagulation and thus represents an interesting model for the development of new treatment modalities.

• a) Replacement therapy : the aim of replacement therapy in DIC is to replace the deficiency due to the consumptionof platelets, coagulation factors and inhibitors in order to prevent or arrest the hemorrhagic episodes (Bick RL: Disseminated intravascular coagulation: objective clinical and laboratory diagnosis, treatment and assessment of therapeutic response. Semin Thromb Haemost 1996, 22:69-88). Platelet concentrates and fresh frozen plasma (FFP) were, in the past, used very cautiously because of the fear that they might "feed the fire" and worsen thrombosis in patients with active DIC. However, this fear was not confirmed by clinical practice and nowadays replacement therapy is a mainstay of the treatment of patients with significant bleeding and coagulation parameters compatible with DIC. Transfusion of platelet concentrates at 1–2 U/10 Kg body weight should be considered when the platelet count is less than 20 × 10⁹/L or if there is major bleeding and the platelet count is less than 50 × 10⁹/L. When there is significant DIC-associated bleeding and fibrinogen levels are below 100 mg/dL, the use of FFP, at a dose of 15–20 mL/Kg, is justified. Alternatively, fibrinogen concentrates (total dose 2–3 g) or cryoprecipitates (1 U/10 Kg body weight) may be administered. However, FFP should be preferred to specific coagulation factor concentrates since the former contains all coagulation factors and inhibitors deficient during active DIC and lacks traces of activated coagulation factors, which may instead contaminate the concentrates and exacerbate the coagulation disorder.
• b) Anticoagulants : the role of heparin in the treatment of DIC remains controversial^{ref1, ref2, ref3, ref4, ref5} [Hoyle CF, Swisky DM, Freedman L, Hayhoe GFJ: Beneficial effect of heparin in the management of patients with APL. Br J Hematol 1988, 68:283-289; Sakuragawa N, Hasegawa H, Maki M, Nakagawa M, Nakashima M: Clinical evaluation of low-molecular-weight heparin (FR-860) on disseminated intravascular coagulation (DIC) – a multicenter co-operative double blind trial in comparison with heparin. Thromb Haemost 1993, 72:475-500; Majumdar G: Idiopathic chronic DIC controlled with low-molecular-weight heparin Blood Coagul Fibrinol 1996, 7:97-98]. In fact, although from a theoretical point of view interruption of the coagulation cascade should be of benefit in patients with active DIC^ref, the clinical studies carried out so far have not been conclusive and indeed have often yielded contradictory results^ref. However, on the basis of the few data available in the literature, heparin treatment is probably useful in patients with acute DIC and predominant thromboembolism, such as those with purpura fulminans^{ref1, ref2}. The use of heparin in chronic DIC is better established and it has been successfully employed in patients with chronic DIC associated with those diseases in which recurrent thrombosis predominates, such as solid tumors, hemangiomas, and dead fetus syndrome (Majumdar G: Idiopathic chronic DIC controlled with low-molecular-weight heparin. Blood Coagul Fibrinol 1996, 7:97-98). The role of heparin in the treatment of DIC associated with acute promyelocytic leukemia (APL) is another controversy, since some authors support its use whereas other studies failed to demonstrate its efficacy^{ref1, ref2} [Hoyle CF, Swisky DM, Freedman L, Hayhoe GFJ: Beneficial effect of heparin in the management of patients with APL. Br J Hematol 1988, 68:283-289]. However, the use of heparin in this setting has declined in the last few years thanks to the introduction of all-trans retinoic acid therapy which has led to the reduction of APL-associated coagulopathy. Heparin is usually given at relatively low doses (5–10 U/Kg of body weight per hour) by continuous intravenous infusion and may be switched to subcutaneous injection for long-term outpatient therapy (i.e. for those patients with chronic DIC associated with solid tumors). Alternatively, low-molecular-weight heparin may be used, as supported by the positive results in both experimental and clinical DIC studies^{ref1, ref2} [Sakuragawa N, Hasegawa H, Maki M, Nakagawa M, Nakashima M: Clinical evaluation of low-molecular-weight heparin (FR-860) on disseminated intravascular coagulation (DIC) – a multicenter co-operative double blind trial in comparison with heparin. Thromb Haemost 1993, 72:475-500; Majumdar G: Idiopathic chronic DIC controlled with low-molecular-weight heparin. Blood Coagul Fibrinol 1996, 7:97-98]. Experimental and clinical studies have also shown the potential role of danaparoid sodium, a low molecular weight heparinoid, in the treatment of DIC^{ref1, ref2, ref3}. A newer anticoagulant agent with direct thombin inhibitory activity, recombinant hirudin (r-hirudin)^{ref1, ref2}, was recently shown to be effective in treating DIC in animal studies, although a study of the effect of this thrombin inhibitor in a sheep model of lethal endotoxemia showed no benefit^ref. Preliminary experimental human studies proved that this drug attenuated endotoxin-induced coagulation activation^ref. Since activation of the coagulation cascade during DIC occurs predominantlythrough the extrinsic pathway, theoretically the inhibition of tissue factor should block endotoxin-associated thrombin generation^ref. In vivo experiments in baboon models of lethal DIC showed that TFPI is a potent inhibitor of sepsis-related mortality^ref. De Jonge and colleagues^ref first demonstrated in humans that recombinant TFPI dose-dependently inhibits coagulation activation during endotoxemia. Recombinant TFPI was evaluated in a phase II randomized trial in patients with severe sepsis^ref. Although the study did not have the statistical power to demonstrate a survival benefit, it did show a trend toward a reduction in 28-day all-cause mortality together with an improvement in organ dysfunction in the group of patients treated with the recombinant TFPI. No evidence of a survival advantage was observed in patients with severe sepsis who received recombinant TFPI in a recent phase III large clinical trial^ref. Inhibition of the tissue factor/factor VIIa pathway is an another strategy that has been explored. Moons and colleagues demonstrated the efficacy of recombinant nematode anticoagulant protein c2 (NaPc2), a potent and specific inhibitor of the ternary complex between tissue factor/factor VIIa and factor Xa, in inhibiting coagulation activation in a primate model of sepsis^ref. Other authors have experimented with anti-tissue factor/factor VIIa antibodies in animal models with promising results^ref.
• c) Restoration of anticoagulant pathways : since patients with active DIC have an acquired deficiency of coagulation inhibitors, restoration of the physiologic anticoagulation pathways seems to be an appropriate aim of the treatment of DIC^ref. Considering that antithrombin (AT) is the primary inhibitor of circulating thrombin, its use in DIC is certainly rational^ref. Recent studies in animals and humans with severe sepsis have demonstrated that antithrombin also has anti-inflammatory properties (reduction of C-reactive protein and IL-6 levels), which may further justify its utilization during DIC^ref [Okajima K, Uchiba M: The anti-inflammatory properties of anti-thrombin III: new therapeutic implications. Semin Thromb Haemost 1998, 24:27-32]. The administration of antithrombin concentrates infused at supraphysiologic concentrations was shown to reduce sepsis-related mortality in animal models^ref. Several small clinical trials have been conducted in humans, mostly in patients with sepsis-related DIC, and have shown beneficial effects in terms of improvement of coagulation parameters and organ function^{ref1, ref2}. An Italian multicenter, randomized, double-blind study conducted in 1998 by Baudo et al.^ref, evaluating the role of antithrombin in patients with sepsis or post-surgical complications, showed a net beneficial effect on survival in those patients receiving the concentrate. These findings were confirmed in 1999 by Levi et al. in their meta-analysis of all so far published human clinical trials of antithrombin treatment of DIC^ref. By contrast, a large randomized, controlled multicenter trial of supraphysiologic doses of AT concentrates conducted in 2144 patients with sepsis and DIC did not show a beneficial effect of antithrombin treatment^ref. However, a retrospective analysis of the same trial showed that the subgroup of patients who did not receive concomitant heparin had a potential benefit from antithrombin III in terms of mortality reduction^ref. Based on the fact that the protein C system is impaired during DIC some authors have investigated the therapeutic efficacy of exogenous administration of this protein in patients with DIC^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9, ref10, ref11, ref12} [Bernard GR, Hartman DL, Helterbrand JD, Fisher CJ: Recombinant human activated protein C (rhAPC) produces a trend toward improvement in morbidity and 28-day survival in patients with severe sepsis. Crit Care Med 1998, 27:S4]. The infusion of activated protein C (APC) concentrates was shown to prevent DIC and mortality in an animal model of sepsis^ref. A study conducted in 1998 on patients with severe sepsis suggested a trend toward improved survival in the group treated with APC [Bernard GR, Hartman DL, Helterbrand JD, Fisher CJ: Recombinant human activated protein C (rhAPC) produces a trend toward improvement in morbidity and 28-day survival in patients with severe sepsis. Crit Care Med 1998, 27:S4]. In a dose-ranging clinical trial, 131 patients with sepsis received recombinant human APC by continuous infusion at doses ranging from 12 mg/Kg/hour to 30 mg/Kg/hour or placebo^ref. A 40% reduction in mortality was observed in those patients who received the higher doses of activated protein C. Similarly, another recent multicenter clinical trial^ref determined that treatment with recombinant human APC, given intravenously at a dose of 24 mg/Kg of body weight per hour, significantly reduced mortality in patients with severe sepsis, in spite of a higher rate of serious bleeding in the APC-treated group. A double-blind randomized trial compared the safety and efficacy of APC and unfractionated heparin in the treatment of DIC and concluded that the former improved DIC, and finally the survival, more efficiently than did heparin^ref. The recently published results of the trial conducted by the Human Recombinant Activated Protein C Worldwide Evaluation in Sepsis (PROWESS) Study Group showed a significant reduction in 28-day mortality and a quicker resolution of organ dysfunction in the group of patients with severe sepsis treated with APC^{ref1, ref2}. These results were confirmed by the ENHANCE trial which also suggested that recombinant APC might be more effective is therapy is started earlier^ref. By contrast, a very recent trial on 2640 patients with severe sepsis and a low risk of death (defined by an APACHE II score <25 or single organ failure) did not find a statistically significant difference in 28-day mortality rate between the placebo and APC-treated groups^ref, suggesting that APC is of benefit only in patients at high risk of death from sepsis.Ongoing studies are focusing on the concomitant use of heparin in patients with DIC who receive activated protein C^ref.
• d) Other agents : recombinant factor VII activated (rFVIIa) may be used in patients with severe bleeding who are not responsive to other treatment options. Bolus doses of 60–120 ?g/Kg, possibly repeated after 2–6 hours, have been found to be effective in controlling refractory hemorrhagic episodes associated with DIC^{ref1, ref2}. Antifibrinolytic agents, such as epsilon-aminocaproic acid or tranexamic acid, given intravenously at a dose of 10–15 mg/Kg/h, are occasionally used in patients resistant to replacement therapy who are bleeding profusely or in patients with disease states associated with intense fibrinolysis (prostate cancer, Kasabach-Merrit syndrome, acute promyelocytic leukemia)^ref. However, since these agents are very effective in blocking fibrinolysis, they should not be administered unless heparin has been previously infused in order to block the prothrombotic component of DIC. The use of these drugs in APL has declined in the last few years, given the efficacy of all-trans-retinoic-acid in preventing the majority of the hemorrhagic complications of this malignancy^ref. The advances in the understanding of the pathophysiology of DIC have resulted in novel preventive and therapeutic approaches to this disease. Based on the fact that tissue inflammation is a fundamental mechanism in DIC associated with sepsis or major trauma, some researchers have successfully employed the combined blockade of leukocyte/platelet adhesion and coagulation in a murine model by using antiselectin antibodies and heparin and have suggested the potential clinical use of such a strategy^ref. Based on the same rationale, other researchers have demonstrated that the administration of recombinant IL-10, an anti-inflammatory cytokine which may modulate the activation of coagulation, completely abrogated endotoxin-induced effects on coagulation in humans^ref. By contrast, the use of monoclonal antibodies against tumor necrosis factor has shown disappointing or at best modest results in septic patients^{ref1, ref2, ref3}. More recently, Branger and colleagues^ref found that an inhibitor of p38 MAPK, an important component of intracellular signaling cascades that mediate the inflammatory response to infectious and non-infectious stimuli, attenuated the activation of coagulation, fibrinolysis and endothelial cells during human endotoxemia. Finally, although studies using antibodies against the receptor for bacterial endotoxins (CD14) produced positive results^ref, other studies using endotoxin antibodies failed to improve outcome^{ref1, ref2}.
Symptoms & signs : skin and mucous hemorrhages, shock, metabolic acidosis, ARDS, MOF, thromboses in subacute DIC
Laboratory examinations :
• no hemolysis
• reduced antithrombin and protein C
• [fibrinogen]_plasma may initially appear normal because it is an APP
• all other [coagulation factors]_plasma are decreased
• enlengthening of both aPTT and INR is due also to inhibition by FDPs
• paracoagulation test (protamine sulfate or ethanol tests) shows circulating fibrin monomers
Differential diagnosis :

	acute DIC	chronic DIC	primary fibrinolysis	TTP	chronic hepatitis
incidence	common	common	very rare	rare	common
INR	very increased	normal or increased	increased	normal	normal or increased
aPTT	very increased	normal or increased	increased	normal	normal or increased
fibrinogen	very reduced	normal (compensated by chronic inflammation) or reduced	very reduced	normal	reduced, normal or increased
factor VIII	reduced	normal or reduced	normal or reduced	normal	normal
antithrombin III	reduced	normal or reduced	reduced	normal	reduced
euglobulin lysis time	normal or reduced	normal or reduced	very reduced	normal	normal
plasminogen	reduced	reduced	very reduced	normal	normal or reduced
D-dimer	+++ (> 2,000 mg/ml)	+	+/-	+/-	+/-
other FDP	+++	+	++++		+/-
platelets	very reduced	normal or reduced (other than in acute promyelocytic leukemia with hyperfibrinolysis)	normal	very reduced	normal or reduced
RBC alterations	schistocytosis	mild schistocytosis	-	marked schistocytosis	frequent macrocytosis

Other D-dimer elevation : surgery, reabsorbing hematomas, deep venous thrombosis, pulmonary thrombembolism, liver cirrhosis, renal failure
FDP >15 mg/mL is the most effective to differentiate leukemia-associated DIC from non-DIC, resulting in diagnostic sensitivity and specificity of 92% and 96%, respectively^ref.
Therapy :
• heparin (in purpura fulminans or limb ischemia : i.v. infusion 300-500 U/hr) until increase in platelet.
• antifibrinolytic drugs in bleeding patients
• replacement therapy
• platelet concentrates (until > 20,000/ml; > 30,000/ml if active bleeding)
• fresh frozen plasma (15-20 ml/kg until fibrinogen > 100 mg/dl); if uneffective => fibrinogen concentrates (2-3 g), which unfortunately contain also activated coagulation factors and do not contain natural coagulation inhibitors
• antihrombin III ? : high-dose AT without concomitant heparin in septic patients with DIC may result in a significant mortality reduction^ref
• rHu-APC ?
• gabexate mesilate^ref
• tissue factor pathway inhibitor (TFPI) ?
• increased clearance of coagulation factors
• factor X deficiency

Aetiology : amyloidosis
• factor XI deficiency

Aetiology :
• Gaucher's syndrome
• nephrotic syndrome
• autoimmunity (autoAbs = acquired inhibitors) => acquired hemophilia (AH)
• anti-factor VIII antibodies (acquired hemophilia A)
• anti-factor IX antibodies (acquired hemophilia B)
• anti-vWF antibodies
• anti-factor V antibodies
• anti-fibrinogen antibodies
• anti-factor XIII antibodies
• anti-phospholipid antibody syndrome
• acquired thrombophilic coagulopathies : deficiency of anticoagulant factors
• acquired deficiency of antithrombin III:

Aetiology :
• physiological deficiency :
• immaturity and newborns
• elderlies
• consumption coagulopathies
• DIC, sepsis, shock
• preeclampsia
• surgery
• acute promyelocytic leukemia
• massive venous thrombosis
• nephropathies
• nephrotic syndrome
• hemolytic-uremic syndrome
• hepatopathies
• acute hepatitis
• chronic hepatitis and cirrhosis
• hepatocellular carcinoma
• gastrointestinal disease
• inflammatory bowel disease
• protein-losing enteropathy
• drugs
• heparin
• L-asparaginase
• estrogens and tamoxifen
• hemodilution
• hemodialysis
• plasmapheresis
Therapy : replacement therapy is useless
• hypercoagulability

Aetiology :
• reduced aPTT
• 
  
• reduced INR
• excessive use of procoagulant drugs
• protein C deficiency
• protein S deficiency
• antithrombin III deficiency
• antiphospholipid antobody syndrome
• Leiden factor V mutation
• G20210 prothrombin mutation
• systemic malignancy
• sickle cell anemia (SCA)
• b-thalassemia and hemoglobin E-thalassemia disease
• polycythemia vera
• systemic lupus erythematosus (SLE)
• hyperhomocysteinemia
• thrombotic thrombocytopenic purpura (TTP)
• disseminated intravascular coagulation (DIC)
• dysproteinemia
• nephrotic syndrome
• thrombocytosis
• inflammatory bowel diseases (IBDs)
• estrogens :
• oral contraceptives
• grapefruit juice can augment the bioavailability of ethinylestradiol by inhibiting CYP3A4, a cytochrome P450 enzyme densely expressed in the wall of the small bowel. The enzyme metabolises many drugs, including ethinylestradiol, dihydropyridines, and statins. Inhibition of CYP3A by grapefruit juice most likely occurs through increased enzyme degradation. With an effective half-life of about 12 h, a cumulative effect of daily grapefruit juice consumption can occur. The magnitude of effect varies; those with high inherent bowel wall enzyme content show the largest enzyme reduction with juice treatment, resulting in an increase in peak drug concentration of up to 6 times (DG Bailey, MO Arnold and JD Spence, Grapefruit juice-drug interactions, Br J Clin Pharmacol 46 (1998), pp. 101–110)^ref
• dehydratation
Symptoms & signs : arterial thrombosis and venous thrombosis
Laboratory examinations :
• protein C
• protein S
• activated protein C resistance
• homocysteine
• PA
• INR
• aPTT
• aPTT ratio
• AT-III
• lupus anticoagulant
• anti-cardiolipin antibodies
• dosage of factor II, VII, VIII
• MTHF reductase mutations (A1298C and C677T)
• factor V Leiden (H1299R and G1691A) mutation
• factor II mutation
• fibrinogen mutation (455G>A)
• factor XIII (V34L)
• tPA
• PAI 4G/5G
• apoA and apoC dosage
Therapy : anticoagulant drugs or antiplatelet drugs
• hypocoagulability

Aetiology :
• normal aPTT and INR : factor XIII deficiency
• increased aPTT and normal INR
• excessive administration of heparin
• anti-phospholipid antibody syndrome
• anti-factor VIII antibodies (acquired hemophilia A)
• anti-factor IX antibodies (acquired hemophilia B)
• anti-vWF antibodies
• vWD
• hemophilia A
• increased INR and normal aPTT
• excessive administration of dicumarols
• liver failure
• factor VII deficiency
• increased INR and aPTT
• DIC
• hyperfibrinolysis :
• primary generalized hyperfibrinolysis
• cardiocirculatory failure
• surgical trauma
• heat stroke
• severe hepatopathies
• acute pancreatitis
• cancer, expecially prostate cancer, can directly secrete t-PA
• thrombolytic drugs
• secondary hyperfibrinolysis : DIC
• localized hyperfibrinolysis :
• dissection of aortic aneurysm
• cavernous hemangioma
• nephropathies, including acute graft rejection
Symptoms & signs : hemorrhages
Laboratory examinations :
• bleeding time test : a test of bleeding time (the duration of bleeding that follows puncture of the skin), assessing capillary function and platelet function, such as ...
• Duke's test : a type of bleeding time test in which the incision is made in the earlobe (n.v. < 4 min)
• Ivy's method or test : a bleeding time test in which incisions are made on the forearm, a sphygmomanometer is inflated around the upper arm, and the time until cessation of bleeding is recorded
• Marx method : (n.v. 1-5 min)
• Simplate method : (n.v. < 7 min)
• aspirin tolerance test : any of various bleeding time tests in which aspirin is administered and its effect on bleeding time is assessed; aspirin prolongs bleeding time in patients with von Willenbrand's disease and certain other platelet disorders.
• template method : a bleeding time test in which a template with a standard-sized slit is laid on the patient's forearm and an incision is made through the slit with a standard-sized knife, keeping arterial arm pressure to 40 mmHg
• platelet function analyzer (PFA)
Aspirin and anti-inflammatory medication will prolong the bleeding time result. The patient should be off aspirin for at least 10 days prior to testing. Bleeding time results will be affected when the platelet count is < 100,000/ml
It is prolonged in :
• thrombocytopenia and thrombocytopathies
• von Willenbrand's disease
• congenital afibrinogenemia
• factor V deficiciency or Owren's parahemophilia
• acetylsalicilic acid, platelet antiaggregants, and some antibiotics
• vascular purpuras
• functionality of intrinsic pathway (prekallikrein, high-molecular-weight kininogen, XII, XI, IX or VIII) and common pathway (X, V, II and I) of coagulation
• whole blood clotting or coagulation time ~ 8÷15' from collection into a vacutainer kept at T=37°C (Lee-White technique). Residual variables : agitation, recipients, [PF3] (~ PLT ~ 1/centrifugation speed) and contact activation surface.
• Howell recalcification time ~ 80÷120". Idem + blood:Na⁺citrate^-3.8% 1:9 => calcium ion is replaced in anticoagulated platelet-rich plasma by adding CaCl₂ in large excess. Residual variables : [PF3] (~ PLT ~ 1/centrifugation speed) and contact surface.
• partial thromboplastin time (PTT) ~ 40÷60". Idem + adding platelet substitutes (e.g., brain cephalin, soybean or other phospholipids similar to PF3). Residual variable : contact activation surface.
• activated PTT (aPTT / APTT) ~ 25÷35". Idem + contact activation surface is maximized with kaoline or ellagic acid.
• aPTT ratio (aPTR). For 3 weeks blood collection on 20÷40 healthy people near age 40 is made to obtain an average plasma on which aPTT is determined twice. aPTR = patient's aPTT / pool's aPTT ~ 0.7÷1.1
• functionality of extrinsic pathway (VII) and common pathway (X, V, II and I)
• Quick's test or time (QT) / one-stage prothrombin time (PT) test ~ 11÷15" = the rate at which prothrombin is converted to thrombin. As in Howell recalcification time (citrated blood with added calcium), but also add excess TF. Residual variable : kind of TF (most used rabbit brain acetone extract, Russel viper venom, ..). The test is often used to monitor administration of coumarin-type anticoagulants
• 2-stage prothrombin time test : a method of quantitating prothrombin after tissue thromboplastin and excess factor V have converted it to thrombin, by determining the clotting time of a standard fibrinogen solution to which the previously generated thrombin has been added
• prothrombin consumption test : a test formerly much used to measure the formation of intrinsic thromboplastin by determining the residual serum prothrombin after the completion of blood coagulation.
• prothrombin-proconvertin test : a test formerly used in the control of coumarin-type anticoagulants, employing a saline extract of brain as a thromboplastin and requiring presence of excess blood coagulation factor V
• reptilase time : a test of coagulation time similar to the thrombin time, measuring coagulation time of blood to which reptilase (an enzyme from Russell's viper (Vipera russelli) venom that clots fibrinogen and can be used to determine blood coagulation time) has been added; since reptilase is not affected by the presence of heparin, the test can be used in patients receiving heparin therapy.
• Russell's viper venom time / Stypven time test : a prothrombin test similar to the (one-stage) prothrombin time, but performed with Russell's viper venom (Stypven) as the thromboplastic agent; useful in defining deficiencies of blood coagulation factor X.
• dilute Russell's viper venom time (dRVVT) (IL Test^®). It is unaffected by contact factor abnormalities and FVII deficiency or inhibition. Heparin intereference is neutralized using polybrene.
• prothrombin activity (PA)~ 80÷110 %. For 3 weeks blood collection on 20÷40 healthy people near age 40 is made to obtain an average plasma on which PT is determined twice each at scalar diluitions with Na⁺Cl^- 0.9% : 100%, 50% (1+1), 25% (1+3), 12.5% (1+7), 10% (1+9). Patient's PA is calculated by looking for the pool % activity corresponding to his own PT.
• prothrombin ratio (PR) = patient's PT / pool's undiluited PT ~ 0.85÷1.15 (1.5÷2.5 during heparin therapy)
• international normalized ratio (INR) = PR^{international sensitivity index (ISI)} ~ 2÷3. ISI acts as a corrective factor to compare different TFs.
• thromboplastin generation test : a test formerly used in the detection of defects in formation of prothrombinase and hence deficiencies of the factors involved.
• functionality of factor I :
• thrombin time (TT) / thrombin clotting time (TCT) ~ 11.3÷18.5" = time required for plasma fibrinogen to form thrombin. Add a large excess of exogenous thrombin to citrated plasma; it is prolonged with abnormalities of fibrinogen and in the presence of heparin or of fibrin/fibrinogen degradation products.
Algorythms :
• normal aPTT and INR : dosage of factor XIII
• normal aPTT and TT and increased INR => defect in extrinsic pathway (i.e. factor VII)
• increased aPTT and normal INR and TT :
• => add heparinase
• => aPTT returns normal : wrong blood collection !
• => aPTT remains high => mixing studies (add a same volume of plasma from a donor with normal aPTT)
• if aPTT returns normal : defect in factor XII, XI, IX or VIII
• if aPTT is initially normal but then increases : anti-factor VIII autoAbs
• if aPTT remains increased : anti-factor XII, XI, IX or VIII autoAbs.
The specific factor deficitary in the patient may be identified as that absent in the donor whose plasma is unable to correct patient's aPTT.
• increased aPTT and INR :
• => add heparinase
• => aPTT returns normal : wrong blood collection !
• => aPTT remains high => defect in common pathway (i.e. factor X, V, II or I)
• increased TT => defect in factor I, FDP excess or anti-thrombin autoAbs
• normal TT => defect in factor X, V, II
• defect in factor V : failure of hepatic synthetic function (rise in factor VIII)
The specific factor deficitary in the patient may be identified as that absent in the donor whose plasma is unable to correct patient's aPTT and INR.
Therapy : procoagulant drugs

Copyright © 2001-2014 Daniele Focosi. All rights reserved  |  Terms of use  | Legal notices
About this site  |  Site map  |  Acknowledgements |  Current link partners
 Abbreviations and acronyms  |  Medical terminology  |  Add a link  |  Translate   |  Softwares |  Cite this page!

Rate Us:  10 - The Best 9 8 7 6 5 4 3 2 1 - The Poorest

---

---

Search  Entrez NCBI Web Site ------------- PubMed Gene LocusLink Taxonomy Protein Nucleotide Structure Genome Books CancerChromosomes Conserved Domains 3D Domains GEO Profiles GEO Datasets HomoloGene Journals MeSH NLM Catalog OMIM PMC PopSet PubChem BioAssay PubChem Compound PubChem Substance SNP UniGene UniSTS for

Search  About AltaVista Ask Jeeves Dictionary DirectHit Excite FindWhat Google Google Groups HotBot LookSmart Lycos Metacrawler MetaLocate Northern Light Open Directory Snap Thesaurus Webcrawler Yahoo for

Search Medical Dictionary  for