COAGULATION DISORDERS

MARY GAY BULIYAT, M.D.

 HEMOSTASIS

the hemostatic system maintains a BALANCE

between
PROCOAGULANT and ANTICOAGULANT forces

• Platelet
• Natural
adhesion and
inhibitors of
aggregation
coagulation
• Fibrin clot • Fibrinolysis
formation
 HEMOSTASIS
STEPS:
1. PLATELET ADHESION
2. PLATELET AGGREGATION
3. PLATELET PLUG FORMATION
4. FIBRIN CLOT FORMATION
HEMOSTASIS
COAGULATION
COAGULATION
 COAGULATION DISORDERS
1. HEMOPHILIA and COAGULATION FACTOR
DEFFICIENCIES
• HEMOPHILIA A
• HEMOPHILIA B
2. DISSEMINATED INTRAVASCULAR
COAGULOPATHY
3. COAGULATION DISORDERS OF LIVER DISEASE
HEMOPHILIA
 HEMOPHILIA

• X-linked RECESSIVE hemorrhagic disease due to mutations

in the F8 gene (hemophilia A or classic hemophilia) or F9
gene (hemophilia B)
• 1 in 10,000 MALES worldwide
• 80% of males have Hemophilia A
• ONLY MALES are CLINICALLY AFFECTED
• FEMALES are the CARRIERS
• Family history of the disease is absent in ~30% of cases
• 80% of the mothers are carriers of the de novo mutated allele
 HEMOPHILIA

• CLINICAL MANIFESTATION:
• HEMOPHILIA A and HEMOPHILIA B are CLINICALLY
INDISTINGUISHABLE from each other
• The disease phenotype correlates with the residual activity of
FVIII or FIX and can be classified as severe (<1%), moderate
(1–5%), or mild (6–30%)
• SPECTRUM from asymptomatic to life threatening bleeding
 HEMOPHILIA

• CLINICAL MANIFESTATION:
• MODERATE and SEVERE
• HEMARTHROSIS or SOFT TISSUE HEMATOMA may
occur after TRAUMATIC injury or SPONTANEOUSLY
• MILD
• residual FVIII or FIX activity >25% of normal, the disease
is discovered only by bleeding after major trauma or during
routine pre- surgery laboratory tests
• Infrequent bleeding usually aftermajor trauma or major
surgery
 HEMOPHILIA
• CLINICAL MANIFESTATION:
• EARLY MANIFESTATION in childhood:
• bleeding may present after circumcision or rarely as intracranial
hemorrhages
• more evident when children begin to walk or crawl
• severe form
• most common bleeding manifestations are the recurrent
hemarthroses, affecting every joint but mainly affect knees,
elbows, ankles, shoulders, and hips
• After a joint has been damaged, recurrent bleeding episodes
result in the clinically recognized “target joint,” which then
establishes a vicious cycle of bleeding, resulting in
progressive joint deformity
 HEMOPHILIA

• CLINICAL MANIFESTATION:
• COMPARTMENT SYNDROME
• Caused by expanding hematomas in muscle of distal
parts of the limbs leading to external compression of
arteries, veins, or nerves
• PSEUDOTUMOR SYNDROME
• Retroperitoneal accumulation of large quantities of blood
with formation of masses with calcification and
inflammatory tissue reaction
 HEMOPHILIA

• DIAGNOSIS:
• made after specific determination of FVIII or FIX clotting
activity OR assay
• the global tests of coagulation show only an isolated
prolongation of the aPTT assay
• normal bleeding times and platelet counts
 HEMOPHILIA
• TREATMENT
• FACTOR REPLACEMENT THERAPY
• can be provided either in response to a bleeding episode or as
a prophylactic treatment
• PRIMARY PROPHYLAXIS
• Defined as a strategy for maintaining the missing clotting
factor at levels ~1% or higher on a regular basis in order to
prevent bleeds, especially the onset of hemarthroses.
• Hemophilic boys receiving regular infusions of FVIII (3
days/week) or FIX (2 days/week) can reach puberty without
detectable joint abnormalities
 HEMOPHILIA
TREATMENT
• GENERAL CONSIDERATIONS in the treatment of bleeds:
1. Treatment should begin as soon as possible because symptoms often
precede objective evidence of bleeding
• Superior efficacy of early therapeutic intervention
• Classic symptoms of bleeding into the joint in a reliable patient,
headaches, or automobile or other accidents require prompt
replacement and further laboratory investigation
2. Drugs that hamper platelet function, such as aspirin or aspirin- containing
drugs, should be avoided
• to control pain, drugs such as ibuprofen or propoxyphene are preferred.
 HEMOPHILIA
TREATMENT
• FACTOR REPLACEMENT
• One unit is defined as amount of FVIII (100 ng/mL) or FIX (5
μg/mL) in 1 mL of normal plasma
• One unit of FVIII per kilogram of body weight increases the
plasma FVIII level by 2%

FIX recovery after infusion is usually only

50% of the predicted value

 HEMOPHILIA
TREATMENT
• The FVIII half-life of 8–12 h requires injections twice a day to
maintain therapeutic levels
• FIX half-life is longer, ~24 h, so that once-a-day injection is
sufficient
• Cryoprecipitate is enriched with FVIII protein (each bag contains
~80 IU of FVIII)
• can be used in the absence of FVIII and FIX
 HEMOPHILIA
TREATMENT
• Mild bleeds (uncomplicated hemarthroses or superficial hematomas)
• Initial therapy with factor levels of 30–50%
• Additional doses to maintain levels of 15–25% for 2 or 3 days are
indicated for severe hemarthroses, especially when these episodes
affect the “target joint.”
• Large hematomas or bleeds into deep muscles
• require factor levels of 50% or even higher
• factor replacement may be required for a period of 1 week or longer
 HEMOPHILIA
TREATMENT
• Serious bleeds (oropharyngeal spaces, CNS, and the retroperitoneum)
• require sustained protein levels of 50–100% for 7–10 days
• Prophylactic replacement for surgery
• aimed at achieving normal factor levels (100%) for a period of 7–10
days
• replacement can then be tapered depending on the extent of the
surgical wounds
• Oral surgery
• Associated with extensive tissue damage that usually requires factor
replacement for 1–3 days coupled with oral antifibrinolytic drugs
 HEMOPHILIA
TREATMENT
• COMPLICATIONS of TREATMENT
• INHIBITOR FORMATION
• Development of alloantibodies to FVIII or FIX; Suspected when there is no
response factor relacement at therapeutic doses
• Present in 5 and 10% of all cases; ~20% of severe hemophilia A patients;
and 3–5% of all hemophilia B patients.
• Confirmatory test: aPTT with a mix (with normal plasma
• In most hemophilia patients, a 1:1 mix with normal plasma completely
corrects the aPTT
• In inhibitor patients: aPTT on a 1:1 mix is abnormally prolonged, because
the inhibitor neutralizes the FVIII clotting activity of the normal plasma
• Treatment: immune tolerance induction (ITI)
• daily infusion of missing protein until the inhibitor disappears, typically requiring periods
longer than 1 year, with success rates of approximately 60%.
 HEMOPHILIA
• COMPLICATIONS OF TREATMENT
• Hepatitis C infection and HIV Infection
• Blood transfusion especially in developing countries
• FFP and/ or cryoprecipitate is the source of factor
replacement
• Absence of Vaccine is a problem
• Cancer
• Related to HCV and HIV infection
• Hepatocellular Carcinoma: most common malignancy
among hemophilia patients
 HEMOPHILIA

• MANAGEMENT of HEMOPHILIA CARRIERS

• Are not usually considered to be at risk for bleeding
• Increased for bleeding during traumatic injuries, surgery and delivery
• During pregnancy, both FVIII and FIX levels increase gradually until delivery
• FVIII levels increase approximately two- to threefold compared to non-
pregnant women, whereas an FIX increase is less pronounced
• Imminent risk for bleeding after delivery as there is a rapid fall in the
pregnancy- induced rise of maternal clotting factor levels.
• prevented by infusion of factor concentrate to levels of 50–70% for 3
days in the setting of vaginal delivery and up to 5 days for cesarean
section
• In mild cases, the use of DDAVP and/or antifibrinolytic drugs is
recommended.
DISSEMINATED INTRAVASCULAR
COAGULATION
 DISSEMINATED INTRAVASCULAR COAGULATION
• Clinicopathologic SYNDROME characterized by widespread
INTRAVASCULAR FIBRIN FORMATION in response to excessive
blood protease activity that overcomes the natural anticoagulant
mechanisms
• Most common causes:
• bacterial sepsis
• malignant disorders such as solid tumors or acute promyelocytic
leukemia
• obstetric causes
• Abruptio placenta; septic abortion/ dead fetus syndrome or
amniotic fluid embolism
DISSEMINATED INTRAVASCULAR COAGULATION
(DIC)
DISSEMINATED INTRAVASCULAR COAGULATION
• CLINICAL MANIFESTATION:
• related to the magnitude of the imbalance of hemostasis, to the underlying
disease, or to both
• MOST COMMON FINDINGs:
• BLEEDING ranging from oozing from venipuncture sites, petechiae, and
ecchymoses to severe hemorrhage from the gastrointestinal tract, lung,
or into the CNS
• Purpura Fulminans
• severe form of DIC
• results from thrombosis of extensive areas of the skin
• predominantly affects young children following viral or bacterial infection
DISSEMINATED INTRAVASCULAR COAGULATION
• CLINICAL MANIFESTATION:
• HYPERCOAGULABILITY of DIC manifests as the occlusion
of vessels in the microcirculation and resulting organ failure
• Thrombosis of large vessels and cerebral embolism can also
occur
• Hemodynamic complications and shock are common among
patients with acute DIC
• The mortality ranges from 30 to >80% depending on the
underlying disease, the severity of the DIC, and the age
of the patient
DISSEMINATED INTRAVASCULAR COAGULATION
• CLINICAL MANIFESTATION:
• CHRONIC DIC
• bleeding symptoms are discrete and restricted to skin or
mucosal surfaces
• Systemic Inflammatory Response Syndrome (SIRS)
• from the release of proinflammatory cytokines (interleukin
6 and TNFα)
DISSEMINATED INTRAVASCULAR COAGULATION
• LABORATORY FINDINGS:
• NO SINGLE TEST can establish the diagnosis of DIC
• Prolonged PT and/ or aPTT
• Thrombocytopenia (platelet count <100,000)
• Schistocytes on PBS
• Elevated Fibrin Degradation Products
• Most sensitive test for DIC
*D- dimer is a more specific for the detection of Fibrin BUT
NOT FDP
DISSEMINATED INTRAVASCULAR COAGULATION
• CHRONIC DIC
• CAN OCCUR IN giant hemangioma, metastatic carcinoma, or
the dead fetus syndrome
• Plasma levels of FDP or D-dimers are elevated
• aPTT, PT, and fibrinogen values are within the normal range
or high
• Mild thrombocytopenia or normal platelet counts are also
common findings
• Red cell fragmentation is often detected but at a lower degree
than in acute DIC.
DISSEMINATED INTRAVASCULAR COAGULATION
(DIC)
• TREATMENT:
• The morbidity and mortality associated with DIC are primarily
related to the underlying disease rather than the
complications of the DIC
• The control or elimination of the underlying cause should
therefore be the primary concern
• Attempts to treat DIC without accompanying treatment of
the causative disease are likely to fail.
• INCLUDES control of hemodynamic parameters, respiratory
support, and sometimes invasive surgical procedures
DISSEMINATED INTRAVASCULAR COAGULATION
(DIC)
• TREATMENT:
• ACTIVE BLEEDING
• FFP and/ or Platelet concentrate transfusion
• Low doses of continuous-infusion heparin (5–10 U/kg per h)
• May be effective in patients with low-grade DIC
• Indicated for the treatment of purpura fulminans during the
surgical resection of giant hemangiomas and during removal
of a dead fetus
• In acute DIC, the use of heparin is likely to aggravate
bleeding
VITAMIN K DEFFICIENCY
 VITAMIN K DEFFICIENCY
• Vitamin K mediates post- translational modification of glutamate
residues to γ-carboxylglutamate, a critical step for the activity of
vitamin K–dependent proteins for calcium binding and proper
assembly to phospholipid membranes.
• Deficiency of the functional activity of the enzymes involved in Vit. K
metabolism results in increased risk for bleeding
• Dietary Vitamin K is a rate limiting factor
• Very efficient recycling of Vitamin K
• Gets affected by various conditions
• Use of broad spectrum antibiotics
• Intestinal Malabsorption (anatomic or Functional)
• Chronic Liver Disease
 VITAMIN K DEFFICIENCY
• Vitamin K dependent factors:
• prothrombin, FVII, FIX, and FX
• Prolonged PT first due to FVII shorter half life  prolonged
aPTT
• TREATMENT:
• Parenteral Vitamin K at a total dose of 10 mg is sufficient to
restore normal levels of clotting factor within 8–10 h
• Active Bleeding or Prophylaxis prior to surgery
• FFP transfusion is prefered
COAGULATION DISORDERS ASSOCIATED
WITH LIVER FAILURE
COAGULATION DISORDERS ASSOCIATED WITH
LIVER FAILURE
• LIVER
• site of synthesis and clearance of most procoagulant and
natural anticoagulant proteins and of essential components
of the fibrinolytic system.
• Liver failure is associated with a high risk of bleeding due
to deficient synthesis of procoagulant factors and
enhanced fibrinolysis.
• Thrombocytopenia is common in CLD
• Dysfibrinogenemia is a relatively common finding in patients
with liver disease due to impaired fibrin polymerization
COAGULATION DISORDERS ASSOCIATED WITH
LIVER FAILURE
 COAGULATION DISORDERS ASSOCIATED WITH
LIVER FAILURE
• Prolonged PT, aPTT, and TT depending on the degree of liver
damage
• FDP is normal or slightly increased
• Fibrinogen levels are diminished only in fulminant hepatitis,
decompensated cirrhosis, or advanced liver disease, or in the
presence of DIC
• Prolonged TT and normal fibrinogen and FDP levels suggest
dysfibrinogenemia
• Reduced levels of Fvmay be an indicator of hepatocyte failure
 COAGULATION DISORDERS ASSOCIATED WITH
LIVER FAILURE
• TREATMENT
• FFP is the most effective to correct hemostasis in patients with liver failure
• sufficient to ensure 10–20% of normal levels of clotting factors but not
correction of PT or aPTT
• Vitamin K can be given as it is defficient in liver failure/ CLD
• Platelet concentrates
• indicated when platelet counts are <10,000–20,000/μL to control an
ongoing bleed
• immediately before an invasive proce-dure if counts are <50,000/μL.
• Cryoprecipitate is indicated only when fibrinogen levels are less than 100
mg/mL
 ACQUIRED INHIBITORS OF COAGULATION
FACTORS
• IMMUNE- MEDIATED disease characterized by the presence of an auto-
antibody against a specific clotting factor
• FVIII: most common target of antibody formation, and is sometimes
referred to as acquired hemophilia A
• Inhibitors to prothrombin, FV, FIX, FX, and FXI are also reported.
• Occurs predominantly in older adults (median age of 60 years)
• occasionally in pregnant or postpartum women with no previous
history of bleeding
• In 50% of patients with inhibitors, no underlying disease is identified at
the time of diagnosis.
• Other causes: autoimmune diseases, malignancies (lymphomas,
prostate cancer), dermatologic diseases, and pregnancy.
 ACQUIRED INHIBITORS OF COAGULATION
FACTORS
• Bleeding episodes occur commonly in soft tissues, the gastrointestinal or
urinary tracts, and skin
• Hemarthrosis is rare in these patients
• Retroperitoneal hemorrhages and other life-threatening bleeding may appear
suddenly
• The overall mortality in untreated patients ranges from 8 to 22%, and most
deaths occur within the first few weeks after presentation
• The diagnosis is based on the prolonged aPTT with normal PT and TT
• The aPTT remains prolonged after mixture of the test plasma with equal
amounts of pooled normal plasma for 2 h at 37°C.
 ACQUIRED INHIBITORS OF COAGULATION
FACTORS
• TREATMENT
• Major bleeding is treated with bypass products such as PCC/aPCC or
recombinant FVIIa
• Responsive to immune suppression
• should be initiated early for most cases
• The first choice includes steroid or a combination of steroid with cytotoxic
therapy (e.g., cyclophosphamide)
• complete eradication of the inhibitors in more than 70% of patients
• High- dose intravenous γ-globulin and anti-CD20 monoclonal antibody
have been reported to be effective in patients with autoantibodies to FVIII
• however, there is no firm evidence that these alternatives are superior
to the first line of immunosuppressive drugs.
 THANK YOU!!!

READ HARRISONS PRINCIPLE OF INTERNAL

MEDICINE