Coagulopathy and Bleeding Disorders

Overview of hemostasis:
Hemostasis is the process of blood clot formation at the site of vessel injury. It can be viewed as occurring in four phases:
  • Initiation and formation of the platelet plug
  • Propagation of the clotting process by the coagulation cascade
  • Termination of clotting by antithrombotic control mechanisms
  • Removal of the clot by fibrinolysis
Formation of platelet Plug Platelets are activated at the site of vascular injury to form a platelet plug that provides the initial hemostatic response to stop bleeding. The functional response of activated platelets involves four different processes:
  1. Adhesion — the deposition of platelets on the sub endothelial matrix
  2. Aggregation — platelet-platelet cohesion
  3. Secretion — the release of platelet granule proteins
  4. Procoagulant activity – enhancement of thrombin generation
Clotting Pathway:


The termination phase of the coagulation process involves two circulating enzyme inhibitors, antithrombin (formerly called antithrombin III) and tissue factor pathway inhibitor and a clotting-initiated inhibitory process, the protein C pathway.
Antithrombin (AT) is a circulating plasma protease inhibitor. It neutralizes most of the enzymes in the clotting cascade, especially thrombin, factors Xa, and IXa, as well as factor XIIa and factor XIa, by forming equimolar, irreversible complexes.
It assesses the viscoelastic properties of clot formation in fresh or citrated whole blood in real-time. The test synthesizes information obtained from multiple coagulation tests (PT, PTT, thrombin time, fibrinogen level, and platelet count) into a single read out, providing information regarding clot initiation, clot strength, and fibrinolysis simultaneously.
Bleeding Disorders
  • A general term for a wide range of disorders that lead to poor blood clotting or continuous bleeding . Also known as coagulopathies or clotting disorders
  • 2 categories of bleeding disorders : 
    1. Defects of primary hemostasis
      • Decreased number (thrombocytopenia) or function of platelets( quantitative or qualitative)
      • Impaired platelet plug formation at sites of injury
    2. Defects of secondary hemostasis
    • Deficiency or defects in plasma coagulation system proteins result in decreased fibrin formation at the site of injury.
    • Absence or delay in creation of a definitive hemostatic plug
  • Some conditions are congenital.
    1. von Willebrand’s disease
    2. Hemophilia
  • Others develop during certain illnesses or treatments.
    1. Vitamin K deficiency
    2. Severe liver disease
    3. Disseminated intravascular coagulation (DIC)
    4. Consumptive coagulopathy
    5. Anticoagulant therapy
    6. Thrombocytopenia
Differential Diagnosis
Primary hemostatic (platelet) disorders (Quantitative platelet defects or Qualitative platelet defects)
  • Decreased circulating platelets (thrombocytopenia) due to: 
    1. Decreased marrow production of megakaryocytes
      • Marrow infiltration with tumor, fibrosis
      • Marrow failure: Aplastic, hypoplastic anemias, drug effects
    2. Splenic sequestration due to splenic enlargement or congestion
    3. Increased destruction or consumption of circulating platelets (nonimmune or immune)
      • Vascular prostheses, cardiac valves
      • DIC
      • Sepsis
      • Vasculitis
      • TTP
      • Drug-associated antibodies like Heparin induced antibody
      • Circulating immune complexes (systemic lupus erythematosus, viral agents, bacterial sepsis)
      • Idiopathic thrombocytopenic purpura (ITP)
  • Defects of platelet adhesion
    1. Von Willebrand’s disease
      • Usually autosomal dominant
      • Primary defect is reduced synthesis or chemically abnormal factor VIII–related antigen produced by platelets and endothelium, resulting in abnormal platelet function.
    2. Defects of platelet aggregation : Absence or dysfunction of glycoprotein IIb/IIIa ( Abciximab )
    3. Defects of platelet release : Decreased cyclooxygenase activity
    4. Drug-induced (e.g., aspirin, NSAIDs) via COX inhibition
    5. Uremia
    6. Platelet coating (e.g., penicillin or paraproteins) : PCN antibiotics can cause thrombocytopenia via platelet coating and defective platelet release
  • Systemic disease associated with both quantitative and qualitative platelet defects
    1. Liver disease
    2. Uremia
    3. Myeloproliferative disorders
    4. Dysproteinemias (myeloma, Waldenström’s macroglobulinemia)
    5. Cardiopulmonary bypass
Secondary hemostatic (plasma protein) disorders
  • Hemophilia A due to Deficiency of factor VIII
  •  Hemophilia B due to deficiency of Deficiency of factor IX 
  • Vitamin K deficiency : results in decrease in plasma levels of all the prothrombin complex proteins (factors II, VII, IX, X; proteins C and S).
Laboratory Tests
Bleeding time
  • Not recommended as a screening test
    • May be useful in a patient with bleeding tendencies and normal PT, aPTT, and platelet count
      • If bleeding time is normal, consider factor XIII deficiency or dysfibrinogenemia.
      • If bleeding time is prolonged, measure ristocetin cofactor (RCF) activity.
        • If RCF is reduced, consider vonWillebrand disease.
        • If RCF is normal, consider acquired or hereditary platelet disorders.
Platelet count
Examination of the peripheral blood smear is essential in patients with low platelet counts to exclude the presence of pseudothrombocytopenia due to in vitro platelet agglutination in the presence of EDTA.
  • 150,000–450,000/μL : Normal range
  • 50,000–100,000/μL : Mild prolongation of bleeding time. Bleeding will occur only from severe trauma or other stress.
  • < 50,000/μL:  Easy bruising after minor trauma and bleeding after mucous membrane surgery
  • < 10,000/μL (< 20,000/μL in patients with hematologic malignancy):  Appreciable incidence of spontaneous bleeding, petechiae. Possible intracranial or other spontaneous internal bleeding
Plasma coagulation function
  • Partial thromboplastin time (PTT) :  Screens intrinsic limb of coagulation pathway and all reactions that occur after the activation of factor X
  • PT :  Screens extrinsic limb or tissue-factor dependent pathway and all reactions that occur after the activation of factor X
  • TT ( Thrombin Time): Identifies defect in the conversion of fibrinogen to fibrin
    1. Can be used when both PT and PTT are prolonged
    2. Screens for dysfibrinogenemia or circulating anticoagulants
  • Quantitative fibrinogen determination:  Fibrinogen is synthesized in the liver and is cleaved by thrombin to form fibrin monomers, which polymerize to form a clot.
    1. Can be used when both PT and PTT are prolonged
    2. Hypofibrinogenemia is an important diagnostic laboratory feature of DIC.
  • D-dimer
    1. Reflects plasmin’s breakdown of fibrin
    2. Elevated (> 500 ng/mL) in > 90% of patients with pulmonary embolism
    3. Also used to screen for DIC
Relationship between secondary hemostatic disorders and coagulation test abnormalities
  • Prolonged aPTT only
    1. Decrease in factors XII, high-molecular-weight kininogen, prekallikrein, decrease in factor XI, FVIII and FIX.
    2. Heparin
  • Prolonged PT only
    1. Factor VII deficiency
    2. Vitamin K deficiency, early
    3. Warfarin anticoagulant ingestion
  • Prolonged aPTT and PT
    1. Factor II, V, or X deficiency
    2. Vitamin K deficiency, late
    3. Warfarin anticoagulant ingestion (aPTT prolongation usually mild)
    4. Direct thrombin inhibitors
    5. DIC (Look also for elevated fibrin degradation product level and low fibrinogen level.)
  • Prolonged TT
    1. Dysfibrinogenemia or afibrinogenemia
    2. Heparin-like inhibitors or heparin administration
    3. Dabigatran
  • Prolonged PT and/or PTT not corrected with normal plasma
    1. Bleeding—specific factor inhibitor
    2. No symptoms, or clotting and/or pregnancy loss—lupus anticoagulant
    3. DIC
    4. Heparin or direct thrombin inhibitor
Other tests
  • Mixing studies : used to evaluate a prolonged aPTT or, less commonly PT, to distinguish between a factor deficiency and an inhibitor
  • Specific clotting factor assays
  • Lupus anticoagulants
Diagnostic Procedures
  • Bone marrow biopsy in thrombocytopenia : Total number of megakaryocytes are decreased in disorders of platelet production but elevated in disorders associated with accelerated platelet destruction
Treatment Approach
  • General treatment of hemorrhage
    1. Establish an adequate blood volume to support circulation.
    2. Support blood pressure with isotonic fluids (normal saline).
      • Albumin and fresh-frozen plasma in cirrhotic patients
      • Fresh-frozen plasma and vitamin K (10 mg SC or IV) in cirrhotic patients with coagulopathy
      • Intravenous calcium , if serum calcium level decreases (owing to transfusion of citrated blood)
Specific Treatments
Thrombocytopenia caused by drugs
  • Includes discontinuation of possible offending agents
  • Expect recovery in 7–10 days.
  • Platelet transfusions may be needed if the platelet count is < 10,000/µL (< 20,000/μL in patients with hematologic malignancy).
Heparin-induced thrombocytopenia
  • Includes prompt discontinuation of heparin
  • Prevent thromboses with warfarin or one of the newer direct thrombin inhibitors.
    1. Lepirudin
    2. Argatroban
    3. Fondaparinux
  • Do not substitute low-molecular-weight heparin for unfractionated  heparin in patient with heparin-induced thrombocytopenia.
Chronic ITP
  • Prednisone, initially 1–2 mg/kg daily, then slow tapering to keep the platelet count > 60,000/µL
  •  Intravenous immunoglobulin to block phagocytic destruction may be useful.
  • Rituximab is effective in patient’s refractory to glucocorticoids.
  • Splenectomy, danazol (androgen), or other agents
  • Control of underlying disease most important
  • Platelets, fresh-frozen plasma to correct clotting parameters
  • Heparin may be beneficial in acute promyelocytic leukemia or excessive thrombosis.
Disorders of platelet function
  • Remove or reverse underlying cause
  • Dialysis and/or cryoprecipitate infusions (10 bags/24 hours) may be helpful for platelet dysfunction associated with uremia.
  • Desmopressin may be helpful for bleeding due to platelet dysfunction caused by aspirin or plavix. In both aspirin and uremia, desmopressin releases vWF and help in platelet adhesion.
Hemophilia A
  • Factor VIII replacement for bleeding or before surgical procedure
  • The duration should range from a single dose of factor VIII to therapy twice daily for up to 2 weeks.
Hemophilia B
  • Fresh-frozen plasma or factor IX concentrates, only if indicated by profuse bleeding after trauma or surgical procedure
Von Willebrand’s disease
  • Cryoprecipitate (plasma product rich in factor VIII) or factor VIII concentrate, up to 10 bags bid for 48–72 hours, depending on the severity of bleeding
  • Desmopressin (vasopressin analogue) may benefit some patients.
Vitamin K deficiency
  • Vitamin K, 10 mg SC or slow IV
Liver disease
  • Fresh-frozen plasma
  • Vitamin K, 10 mg SC or IV
  • When the PT is prolonged and the aPTT is normal, think of factor VII deficiency. The major causes of factor VII deficiency are warfarin therapy, vitamin K deficiency, and liver disease.
  • When the aPTT is prolonged and the prothrombin time is normal, think of deficiencies in factors VIII, IX, XI, and XII. The major causes of prolonged aPTT with a normal PT are heparin therapy, the presence of a lupus anticoagulant or other factor inhibitor, and von Willebrand’s disease.
  • Heparin acts by activating Anti-thrombin and inhibiting thrombin and factor Xa
  • Low-molecular-weight forms of heparin often are not large enough to bind thrombin and antithrombin III together. Thus, low-molecular-weight heparins generally act solely by inactivating factor Xa.
  • Warfarin acts by inhibiting the synthesis of Vit.K dependent factors- 2,7,9,10, protein C & S
  • All of the procoagulants are synthesized in the liver except factor VIII and von Willebrand factor (VWF) (synthesized in megakaryocytes and endothelial cells).
  • After initiation of warfarin therapy, factor VII is the first clotting factor to disappear. However, full anticoagulation may take 4 days until levels of factors II, IX, and X also decrease.
  • If the protein C level falls too low before anticoagulation takes place, a paradoxical hypercoagulable state can attend the initiation of warfarin therapy, producing so-called "Coumadin necrosis."
  • Factor VIII is synthesized both in liver and endothelial cells outside of liver. Hence, its levels are not low (may be higher) in liver cirrhosis. However, in DIC factor VIII levels are low.
  • The clotting test most frequently prolonged in the setting of uremia is the bleeding time.
  • The most common hemostatic defects in patients with HIV infection are thrombocytopenia and acquired circulating anticoagulants (which prolong the aPTT).
  • While heparin, LMW heparin, and fondaparinux should, in theory, prolong the PT because they inhibit thrombin, most PT reagents contain heparin-binding chemicals that block this effect. At heparin concentrations above 1 unit/mL, these heparin-binders may become saturated, and heparins may prolong the PT.
  • Anti-factor Xa activity can be measured using a functional assay to determine the adequacy of anticoagulation in patients receiving agents that interfere with factor Xa activity (eg, heparin, low molecular weight [LMW] heparins, rivaroxaban, apixaban). However, the direct factor Xa inhibitors (eg, rivaroxaban, apixaban) do not require routine monitoring in practice.
Coagulation abnormalities in patients with liver disease
Liver disease causes both prothrombotic and coagulopathic states.
  • Increased bleeding risk — Decreased production of non-endothelial cell-derived coagulation factors (eg, factors II, V, VII, IX, X, XI, XIII) is only one component of the coagulation process that disrupts hemostasis. Thrombocytopenia, altered platelet function, platelet inhibition by nitric oxide, abnormalities of fibrinogen, and decreased thrombin activatable fibrinolysis inhibitor (TAFI) all contribute to an increased bleeding risk.
  • Increased thrombotic risk — Decreased levels of the liver-synthesized natural anticoagulant proteins C and S, decreased antithrombin levels, decreased plasminogen, and elevated levels of endothelial cell-derived factor VIII and von Willebrand factor (vWF) favor thrombosis formation.
The relative balance or imbalance in these patients is not reflected in conventional indices of coagulation, such as the prothrombin time (PT), activated partial thromboplastin time (aPTT) or International Normalized Ratio (INR). There is now convincing evidence disproving the common misconception that liver disease patients are "auto-anticoagulated".
Decreased thrombopoietin (TPO) levels, splenic sequestration of platelets due to portal hypertension, auto-antibody destruction of platelets, and bone marrow suppression due to underlying liver disease can all contribute to thrombocytopenia in liver cirrhosis.
Tests of coagulation in liver disease
  1. PT/PTT/INR are all elevated.
  2. Fibrinogen levels are increased
  3. Factor 8 levels are increased
  4. Platelets are decreased
Anti-platelet and anticoagulant therapy — Therapeutic anticoagulation is occasionally needed in patients with cirrhosis and coagulopathy although the management of therapy with warfarin can be difficult because of the baseline coagulopathy as measured by the INR. The best indicator of therapeutic anticoagulation levels in patients with cirrhosis is probably measurement of anti-factor Xa activity following the use of heparin products.
Vitamin K deficiency
  • Vitamin K deficiency
    1. Acquired disorder of blood coagulation
    2. Characterized by easy bruising and bleeding
    3. Deficiency causes a decrease in plasma levels of all the prothrombin complex proteins (factors II, VII, IX, X; proteins C and S).
    4. Deficiency is caused by:
      • Inadequate dietary intake (cabbage, cauliflower, spinach, soybeans, cereals are rich sources)
      • Use of broad-spectrum antibiotics.
      • Disease or surgical interventions that affect the ability of the intestinal tract to absorb vitamin K, either through anatomic alterations or by changing the fat content of bile salts and pancreatic juices in the proximal small bowel
      • Loss of storage sites due to hepatocellular disease
      • Chronic liver diseases such as primary biliary cirrhosis
    • Altered bacterial flora in the gut (a source of vitamin K synthesis)
    • Drugs that interfere with vitamin K (cholestyramine, salicylates, isoniazid)
    • Alcoholism
Risk Factors
  • Vitamin K deficiency
    • Acute vitamin K deficiency is particularly common in patients recovering from biliary tract surgery who have no dietary intake of vitamin K, patients who have T-tube drainage of bile and are on broad-spectrum antibiotics
    • Vitamin K deficiency also is seen in chronic liver disease, primary biliary cirrhosis and malabsorption states
Laboratory Tests
  • Vitamin K deficiency
    1. Early :  because of the rapid fall in factor VII, patients with mild vitamin K deficiency may have a prolonged PT and a normal PTT.
    2. Later : As the levels of the other factors fall, the PTT also will become prolonged.
    3. Fibrinogen, thrombin time, platelet count, and bleeding time are in the normal range.
Treatment Approach
Vitamin K deficiency
  • Vitamin K:  Parenteral administration of 10 mg vitamin K restores vitamin K levels in the liver rapidly and permits normal production of prothrombin complex proteins within 8–10 hours.
  • Correct the underlying cause of vitamin K deficiency.
Presence of ongoing bleeding or a need for immediate correction before an invasive procedure
  • Replacement with FFP
  • Reversal of excessive anticoagulant therapy with warfarin or warfarin-like drugs
  1. Vitamin K (1 mg orally or by intravenous injection) for asymptomatic patients
  2. This strategy can diminish the risk of bleeding while maintaining therapeutic anticoagulation for an underlying prothrombotic state.
  • Women who appear to have hemophilia may have vWD. Hemophilia is an X-linked disorder, but vWD can mimic factor VIII deficiency through failure of defective vWF to prolong factor VIII half-life.
  • In patients with liver cirrhosis and elevated INR, many people give FFP's to reverse the INR, if they need any procedures. However, the INR of the FFP itself is 1.6 and hence, we can't bring the INR to less than 1.6 with FFP's alone.
  • Around 20ml/kg of FFP is needed for hemostasis and to bring coagulation factors to 30% of normal, which is all that is needed for hemostasis. Each bag of FFP is 250ml.
  • PCC can reverse both Coumadin and xarelto but not pradaxa. It can be a 3 factor concentrate or 4 factor concentrate. If it is a 3 factor concentrate, it lacks factor vii and hence, also need 2 bags of FFP and Vit.K.
  • There is no antidote for bleeding due to Bivalirudin or argatroban. Waiting is the only solution and drug wears off in 6 hrs.
  • PCC complex dose is 25-50ml/kg and will be smaller volume than FFP. But, use of PCC complex is associated with higher risk of thrombosis.
  • PCC with 4 factors include all four Vit.K dependent factors( 2,7,9,10)
  • FFP contains factors 2, 5, 7,9,10 and 11.
  • In massive blood transfusions, it’s usually customary to give 1 ffp for every 2-4 PRBC. This is not evidence based and in Europe they actually follow TEG. Also, fibrinogen should be supplemented to above 150-200.
  • In CNS bleeds, transfuse platelets to above 100. 

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