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 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
• 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
• 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, 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
• 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.
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, dosage of prekallikrein
• HMWK / Flaujeac factor deficiency

Aetiology : autosomal recessive mutations
Laboratory examinations : prolonged aPTT, 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
Therapy : none required
• congenital dysfibrinogenemia
• thrombin hyperactivity / prothrombin G20210A

Epidemiology : prevalence = 2%
Aetiology : autosomal dominant mutations of thrombin
Symptoms & signs : RR = 3 for DVT
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
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 (> 150%)

Epidemiology : prevalence = 11%
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 diseaase, 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 died 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
Pathogenesis : excess of tissue factor in peripheral blood and systemic inflammation (IL-1, IL-6, and TNF-a) => uncontrolled generation of thrombin
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	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
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 ?
• rHu-APC ?
• 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)
• oral contraceptives
• 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
• factor V Leiden mutation
• factor II mutation
• tPA
• PAI
• 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
• 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
• 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)
It is prolonged in :
• thrombocytopenia and thrombocytopathies
• von Willenbrand's disease
• congenital afibrinogenemia
• 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
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

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