Disorders of Secondary Hemostasis

3 secondarily acquired disorders

1. DIC 2. primary fibrinolysis 3. liver disease

2 forms of autoimmune inhibitors of factor 8

1. acquired 8:r/vWD - seen with autoimmune diseases or lymphoproliferative diseases 2. inhibitors of 8:c - as a result of factor transfusions or IgG autoantibodies in patients with amplified immune systems (RA, SLE, drug reactions, post partum, malignant, elderly)

3 disorders of fibrinogen

1. afibrinogenemia 2. hypofibrinogenemia 3. dysfibrinogenemia

2 types of factor 8:C inhibitors

1. alloantibodies - transufsion IgG to full 8:vWF complex - does not interfere with VWF (normal BT) 2. autoantibodies - ACQUIRED HEMOPHILIA, seen in patients with autoimmune disorders like RA, lupus, drug allergies, MM, lymphoproliferative disorders

5 acquired inhibition coagulation disorders

1. autoimmune inhibitors of factor 8 2. acquired inhibition of factor 8 3. factor 10 deficiency 4. vitamin k deficiency 5. hepain bound antithrombin

categories of secondary hemostasis disorders

1. disorders of fibrinogen 2. secondarily acquired disorders 3. inherited factor deficiencies 4. acquired coagulation disorders

11 inherited factor deficiencies

1. hemophilia a 2. hemophilia b 3. hemophilia c 4. vWD 5. Factor 7 deficiency 6. Factor 10 deficiency 7. Factor 5 deficiency 8. Factor 2 deficiency 9. Factor 12 deficiency 10. Fletcher deficiency 11. HMWK deficiency

2 treatment courses for inhibitors

1. with low titer inhibitors - give porcine factor 8 concentrates or high concentrations of 8:c to overwhelm Ab and its binding sites 2. with high titer inhibitors: give steriods, porcine factor 8 concentrates, immunosuppressives, cytotoxics, or plasmapheresis,

normal/adequate activity levels from factors 2, 5 and 10

50-150%

discovery of nonspecific inhibitors/lupus anticoagulants

accidental after increased APTT screening

circulating anticoagulats/inhibitors definition, cause, types

allo or autoantibodies (IgG, IgM, IgA) that develop due to underlying disorders or develop spontaneously 2 types: 1. specific - Ab to a specific factor 2. nonspecific/Lupus anticoagulant - interfere with phospholipids

factor 9 inhibitor cause, symptoms

alloantibodies to factor 9 from transfusions symptoms include hemarthrosis, muscle/soft tissue hemorrhages

HMWK deficiency cause, symptoms, labs

autosomal recessive patients are asymptomatic - no apparent clinical bleeding, no racial predilection increased APTT

dysprothrombinemia definition, cause, treatment

autosomal recessive, qualitative structural defect in prothrombin that causes impaired activity - must distinguish from hypoprothrombinemia for proper therapy treatment includes FFP, prothrombin complex concentrates, or factor concentrates

general factor 13 deficiency physiology

because factor 13 functions as a catalyst for to form bonds between proteins (especially fibrin monomers ), symptoms commonly include initial stoppage of bleeding then recurrence of bleeding more than 36 hours after the initial episode

PT, APTT, TT greatly prolonged

consider presence of heparin before a factor deficiency - test for presence of heparin with protamine sulfate test (protamine sulfate inhibits action of heparin)

liver disease affects on coagulation

decrease in majority of coag factors (produced in liver) and abnormal plt function/production

platelet dysfunction in liver disease

decreased adhesion, abnormal PF3 availability and aggregation to ADP, epinephrine, and thrombin

DIC labs and treatment

decreased platelet count increased PT increased APTT microclots/schistocytes in smear decreased quantitative fibrinogen increased FDP increased D Dimer treat with FFP, cryo, plts, LMWH, remove stimulus

hemophilia a definition, cause, requirements of severity, and complications

deficiency of Factor 8:C - most common hereditary coagulation disorder (X linked recessive) severe = less than 1% normal factor 8:C levels (spontaneous hemorrhage, requires transfusion therapy) moderate = 1-5% normal factor 8:C levels mild = 6-30% normal factor 8:C levels (bleeding only associated with severe trauma or surgery) complications include development of alloantibodies to factor 8:C in 10-15% of deficiencies

DIC definition/physiology

disseminated idiopathic/intravascular coagulation - a consumption coagulopathy characterized by small deposits of fibrin throughout microcirculation resulting in activated coagulation pathways activation of plasminogen can also result in increased FDPs and fragmented RBCs

prothrombinase complex

factor 2 converted to thrombin by action of factors 5a and 10a, platelet factor 3, and ionized calcium on platelet surface

first, mild, moderate, and severe factor deficiencies in liver disease

factor 7 is first to decrease - shortest half life mild decrease in factors 2, 7, 9, 10 (VK) moderate decrease in factors 5 and 8 severe decreases in factor 1 (PT and APTT prolonged, often causes decreased or abnormal fibrinogen molecule)

suspected in patients with no prior history of bleeding problems that present with massive bruising or hematoma

factor 8:c inhibitor/autoantibody

best sample to run factor assays

fresh plasma - freezing and thawing can activate the contact system and start intrinsic pathway, consuming those factors and decreasing the APTT

heparin bound antithrombin

has enhanced ability to bind/inactivate thrombin TT, APTT used to monitor heparin therapy

platelet-related function of factor 5

helps bind factor 10 to platelet surface where it activates prothrombin to thrombin

DIC causes

idiopathic or secondary to large amounts of tissue factor in the blood from hypofibrinogenemic states like pregnancy, metastatic cancers, or promyelocytic leukemia

nonspecific inhibitors/lupus anticoagulants definition, labs, symptoms

immunoglobulins that interfere with phospholipids increased PT increased APTT no correction with mixing studies with NPP symtpoms include a hypercoagulable state

factor 5 deficiency labs and treatment

increased BT in 30% of patients due to platelet-related function of factor 5 normal TT increased PT increased APTT treat with FFP or fresh plasma - no cryo as it there is usually not enough factor 5 in concentrate

vitamin k deficiency labs

increased PT possibly increased APTT normal TT normal fibrinogen

primary fibrinolysis definition, symptoms, and causes

increased levels plasmin trigger increased fibrinolysis symptomatically similar to DIC - initially formed clot that dissovles in 1-2 hours and cause diffuse hemorrhages caused by cirrhosis, shock, metatstatic cancer of prostate, injury to urinary tract, leakage of urokinase from urine into tissue

hypoprothrombinemia cause, symptoms

inherited (autosomal recessive) or acquired (from vitamin k deficiency or coumadin therapy) prothrombin/factor 2 deficiency symptoms are hemorrhagic with levels of 2-25%

suspected in hemophiliacs if transfused factor replacement products appear to have reduced effectiveness OR hemostasis is hard to achieve OR both

inhibitor

acquired inhibition of factor 8 cause

isoniazid drug therapy for TB

symptoms of factor 8:c inhibitor/autoantibody

large hematoma, gross hematuria, pharyngeal/peritoneal/cerebral bleeds

hypofibrinogenemia definition, symptoms

low (less than 100 mg/dL) levels of fibrinogen many patients are asymptomatic but some may display mild bleeding problems

specimen for factor 5 deficiency testing

must be platelet poor ( < 100000) to avoid contamination of plasma factor 5 because of platelet-related function of factor 5

hemophilia c labs and therapy

normal BT normal PT normal TT increased APTT decreased/absent factor 11 assay treatments include replacement therapy - recombinant factor 11 or FFP, ONLY NEEDED PRE-OP (giving too much will increase thrombosis risk via positive feedback loop with thrombin)

hemophilia b labs and treatment

normal BT normal PT normal TT increased APTT low % factor 8 or 9 activity mixing studies correct with NPP and aged serum treatments include infusions with recombinant factor 9, FFP, orprothrombin complex

hemophilia a labs

normal BT normal PT normal TT increased APTT (8:C < 20%) low/absent 8:C activity normal vWF:Ag check for inhibitor with mixing studies (yes if no correction with NPP)

factor 7/proconvertin deficiency labs and treatments

normal BT normal T normal APTT increased PT that is corrected with Russell's viper venom and mixing studies with aged serum treatments included FFP, prothrombin complex concentrate, and vitamin k supplements

factor 10 deficiency labs and treatments

normal BT normal TT increased PT increased APTT increased RVVT or Stypven time variant forms of factor 10 could cause discrepancies between assays treatments could include FFP or prothrombin complex concentrates (vitamin k therapy only effective if cause is deficiency) - only need 10% activity for normal adequate hemostasis

factor 12 deficiency labs

normal PT increased APTT decreased or absent factor 12 assay (normal = 70-140%)

factor 9 inhibitor labs

normal PT increased APTT no correction in mixing study with NPP (unless a mild or moderate inhibitor- double check with 2hr incubation at 37 degrees, which will show true prolongation with mild/moderate inhibitors)

autoimmune inhibitors of factor 8:c labs and treatment

normal PT increased APTT no correction with mixing study treatment - factor 8 concentrates, steroids, immunosuppresives, cytoxic agents, protrhombin-complex concentrates, plasmapheresis in severe cases

general factor 13 deficiency labs & treatment

normal PT, APTT, TT< BT, fibrinogen, plt count low levels of factor 13 found by 5M urea test - dissolving clot after 24 hrs treat with FFP or cryo

hypoprothrombinemia labs and treatment

normal TT variably increased PT variably increased APTT diagnosis is dependent on activity assyas/antigenic concentration of prothrombin treatment includes FFP, prothrombin complex concentrate, factor concentrate, or vitamin K supplements

primary fibronolysis labs

normal platelet count increased PT increased APTT normal smear decreased quantitative fibrinogen increased FDP decreased D Dimer

major lab differences between DIC and primary fibrinolysis

platelet count: decreased in DIC, normal in primary fibrinolysis smear: microclots/schistos in DIC, normal in primary fibrinolysis D Dimer: increased in DIC, normal in primary fibrinolysis

treatment of coagulation problems secondary to liver disease

plt concentrate transfusions, DDAVP, FFP, coljugated estrogen (decreases bleeding tendency after acute episodes)

vitamin k deficiency causes and affects

poor diet, biliary obstruction, intestinal malabsorption, gut sterilization from chronic antibiotics, hemorrhagic disease of the newborn, or coumadin therapy impaired synthesis of factors 2, 7, 9, 10, protein c/s

factor 5 is also known as

proaccelerin or labile factor - rapidly deteriorates at room temperature

dysfibrinogenemia definition, labs, symptoms

qualitative abnormality in structure or function of fibrinogen fibrinogen levels and BT may be normal increased TT some patients are asymptomatic but many have post-operative bleeding episodes or tendencies towards thrombosis

afibrinogenemia definition, symptoms, treatment

quantitative disorder caused by lack of synthesis of factor 1 in liver symtpoms include frequent bleeds of the umbilical cord (1st sign), mucosa, GI, etc treat with cryoprecipitate or FFP

factor 7/proconvertin deficiency cause, symptoms

rare, autosomal recessive symptoms include deep muscle hematomas, hemarthrosis, epistaxis, menorrhagia

acquired factor 10 deficiency cause

rare, but as a result ofthe autoimmune disorder amyloidosis

factor 9 levels over 120%

risk for thrombosis - plasminogen not activated due to removal of binding sites from thrombin-activatable fibrinolysis inhibitor

cause of specific inhibitors

secondary to replacement therapy or transfusions, or can arise spontaneously

prothrombin mutation (G20210A) definition, cause, risk factors

single point chromosome 2 mutation primarily found in caucasian population detected via PCR DNA analysis that results in INCREASED prothrombin concentrations and carries and increased risk of thrombosis heterozygous expression results in an increased risk of venous thromboembolism risk of MI in young women, stroke in young patients

hemophilia a symptoms and treatment

symptoms can include hemarthrosis, hematuria, intracranial bleeds, hematomas, & spontaneous hemorrhages treatments: replacement therapy/transfusions and cryo with concentrated fibrinogen and factor 8 complex

hemophilia b definition, cause, requirements for severity, and complications

AKA Christmas disease - factor 9 deficiency inherited (sex linked) or acquired secondary to liver disease, vitamin k deficiency, or oral anticoagulant therapy severe = less than 1% of normal factor 9 activity mild = 5-25% normal factor 8 activity complications can include development of antibodies in 10% of patients

factor 12 deficiency definition, symptoms

AKA Hageman trait patients are usually asymptomatic- not associated with clinical bleeding and post no surgical risk

hemophilia c definition, symptoms, complications

AKA Rosenthal Syndrome - factor 11 deficiency (< 15%) predominantly (1:8) in ashkenazi jewish population, 1:100000 in other populations symptoms include mild bruising, epistaxis, menorrhagia, hematuria, prolonged postpartum bleeding, dental bleeds, severe hemorrhaging complications include development of alloantibodies or inhibitors

factor 10 deficiency definition and cause

AKA Stewart Prower Disease - extremely rare (1:500000) autosomal recessive quantitative or qualitative abnormality of factor 10

prekallikrein deficiency definition symptoms, labs

AKA fletcher deficiency patients are asymptomatic - no apparent clinical bleeding, no ethnic or racial predilection increased APTT - will progressively shorten increased incubation times

factor 5 deficiency definition, causes

AKA parahemophilia or proaccelerin disease, can be inherited (autosomal recessive) or acquired from formation of specific ab to factor 5 after childbirth or use of fibrin glue in surgery, or secondary to liver disease, carcinoma, TB, DIC, etc

factor 2 deficiency definition, symptoms, types

AKA prothrombin deficiency - extremely rare symptoms are hemorrhagic due to delayed generation of thrombin types: 1. hypoprothrombinemia 2. dysprothrombinemia 3. prothrombin mutation (G20210A)