Hemostasis and bleeding disorders

Bleeding disorders are a group of heterogeneous conditions characterized by defects in hemostasis that lead to an increased susceptibility to bleeding (also known as hemorrhagic diathesis). They are classified into disorders of primary hemostasis (when caused by a platelet abnormality), disorders of secondary hemostasis (when caused by defects in the extrinsic and/or intrinsic pathway of the coagulation cascade), and hyperfibrinolysis (when there is increased clot degradation). Although clinical features may overlap, mucocutaneous bleeding (e.g., epistaxis, petechiae, gastrointestinal bleeding) is associated with disorders of primary hemostasis, and bleeding into potential spaces (e.g., hemarthrosis, muscular bleeding) is characteristic of disorders of secondary hemostasis. The diagnostic workup of a bleeding disorder begins with a detailed clinical assessment the CBC and a coagulation panel. This typically allows the disorder to be classified as one of primary or secondary hemostasis. Specialized studies are then required determine the specific etiology so that treatment can be initiated. Treatment may include transfusion of blood products, replacement of specific coagulation factors, or administration of adjuvant medications (e.g., tranexamic acid or desmopressin).

Overview ^[1][2]

Hemostasis is the physiological process by which a bleeding stops. Its final result is a thrombus (blood clot), which consists of blood cells and fibrin strands. Hemostasis involves the following mechanisms:

• Primary hemostasis
  • Vascular hemostasis: transient vasoconstriction and vWF activation following endothelial injury
  • Platelet hemostasis: adhesion, activation, and aggregation of platelets, which results in the formation of a platelet plug (white thrombus)
• Secondary hemostasis: activation of the coagulation cascade, which results in the formation of a fibrin clot (red thrombus)

Primary hemostasis

• Definition: : processes involved in the formation of a platelet plug (white thrombus) following endothelial injury
• Vascular hemostasis
  • Endothelial injury results in:
    • Neural stimulation reflexes and endothelin release → transient vasoconstriction, leading to:
      • Reduced blood flow
      • Platelet accumulation at the vessel walls
    • Exposure of subendothelial collagen → circulating von Willebrand factor binds to the exposed collagen
  • Von Willebrand factor (vWF): plasma protein that is synthesized by and stored in endothelial cells (in Weibel-Palade bodies) and platelets (in α-granules)
    • Mediates platelet adhesion and aggregation
    • Binds factor VIII (and thereby prevents its degradation)
• Platelet hemostasis
  1. Platelet adhesion: platelets bind to vWF via platelet GpIb receptor at the endothelial injury site
     • Ristocetin normally activates vWF to bind to glycoprotein Ib
  2. Platelet activation: After binding to vWF, platelets change their shape and release mediators that lead to activation of more platelets (positive feedback). These mediators include:
     • Adenosine diphosphate (ADP): promotes adhesion of platelets to endothelium
     • Thromboxane A2 (TXA₂): activates additional platelets and promotes vasoconstriction
     • Calcium: required for secondary hemostasis
     • Platelet-activating factor (PAF): a phospholipid mediator that is produced by platelets and inflammatory cells (e.g., neutrophils, monocytes, macrophages), involved in platelet aggregation and activation and local inflammatory response
  3. Platelet aggregation
     • Mediated by GpIIb/IIIa-receptor and fibrinogen → formation of a white thrombus composed of platelets and fibrinogen
     • A white thrombus is transient, unstable, and easily dislodged. It stabilizes through the process of secondary hemostasis.

Secondary hemostasis

• Definition: : processes that lead to stabilization of the platelet plug; (white thrombus; ) by creating a fibrin network
  • Coagulation cascade: a sequence of events triggered by the activation of the intrinsic or extrinsic pathway of coagulation that results in the formation of a stable thrombus
  • Coagulation factors
    • Substances that interact with each other to promote blood coagulation
    • Activated factors are designated with an “a” (e.g., activated factor VII = factor VIIa).
• Extrinsic pathway of coagulation: triggered by endothelial injury
  1. Tissue factor (factor III) activates factor VII.
     • Tissue factor is expressed on the surface of subendothelial muscle cells and fibroblasts.
     • Factor VII: vitamin K-dependent coagulation factor produced by the liver
  2. Factor VIIa and tissue factor form a complex (TF-FVIIa). This step requires calcium (factor IV) found on the surface of fibrocytes and activated platelets.
  3. TF-FVIIa activates factor X and factor IX.
• Intrinsic pathway of coagulation
  • Exposed collagen, kallikrein, and kininogen (HMWK) activate factor XII.
    • Factor XII (Hageman factor): coagulation factor that also plays a role in inflammatory response by activating the kallikrein system, which leads to the production of bradykinin
    • Factor XIIa activates factor XI.
  • Thrombin activates factor XI and factor VIII.
  • Factor XIa activates factor IX.
  • Factors VIIIa and IXa form a complex (mediated by calcium) that activates factor X.
  • This causes a positive feedback loop of factor X and thrombin activation via the intrinsic pathway.
• Common pathway of coagulation: The extrinsic end intrinsic pathway both end in the common pathway.
  1. Factor Xa and factor Va form a complex (mediated by calcium) that cleaves prothrombin (factor II) to thrombin (factor IIa).
  2. Thrombin cleaves fibrinogen (factor I) into insoluble fibrin (factor Ia) monomers.
  3. Crosslinks of the fibrin network are stabilized by factor XIIIa → formation of a fibrin network → fibrin closely binds to the platelet plug, forming a stable thrombus (secondary thrombus or red thrombus)

The coagulation cascade requires the presence of calcium ions (factor IV).

A helpful way of remembering the coagulation factors of the extrinsic pathway is 3 + 7 = 10: Tissue factor (factor III) and factor VII form a complex that activates factor X of the common pathway.
A helpful way of remembering the coagulation factors of the common pathway is 10/5 = 2 × 1: Factors Xa and Va form a complex that cleaves prothrombin (factor II) to thrombin (IIa). Factor IIa then cleaves fibrinogen (I) into insoluble fibrin monomers (Ia).

Inhibition of hemostasis

In order to prevent hypercoagulability as well as excessive bleeding, activation of the coagulation cascade and the processes that inhibit it occur simultaneously in the circulatory system (procoagulant-anticoagulant balance).

• Tissue factor pathway inhibitor: inhibits tissue factor
• Protein C and protein S: Activated protein C and its cofactor protein S form the activated protein-C complex (APC complex), which inhibits factors Va and VIIIa.
  • Vitamin K-dependent synthesis in the liver
  • Shorter half-life than vitamin K-dependent coagulation factors (relevant for treatment with vitamin K antagonists, e.g., warfarin)
  • Clinical relevance
    • APC resistance
    • Factor V Leiden
    • Protein C deficiency, protein S deficiency
• Antithrombin
  • Degrades thrombin and factors IXa and Xa
  • Activates tissue plasminogen activator (tPA)
  • Clinical relevance: antithrombin III deficiency (e.g., due to liver failure or kidney failure)
• Nonspecific inhibitors: protease inhibitors in plasma (e.g., alpha-1-antitrypsin, alpha-2-macroglobulin)
• Drug-induced: anticoagulant treatment (see “Oral anticoagulants” and “Parenteral anticoagulants”)
• Others
  • Protein Z (factor X inhibitor)
  • Heparin-like glycosaminoglycans (boosts antithrombin)
  • Heparin cofactor II (requires heparin for activation)

Diseases that affect the inhibitors of the coagulation cascade may lead to hypercoagulability.

Overview ^[2]

• Definition: degradation of the fibrin network of thrombi by the enzyme plasmin
• Mechanism
  • Tissue injury leads to the release and activation of plasminogen activators, which convert plasminogen to its active form plasmin.
    • Tissue plasminogen activator (tPA)
    • Urokinase (see fibrinolytics)
  • Plasmin breaks down and deactivates fibrin and fibrinogen → release of fibrin degradation products (e.g, D-dimers)
• Regulation
  • Plasminogen activator inhibitors (e.g., PAI-1) inhibit tPA
  • Plasmin inhibitors (e.g., PPIC)

Fibrinolytic therapy ^[4]

• Agents: Fibrinolytics promote the degradation of thrombi by activating plasminogen to plasmin.
  • Fibrin-specific agents
    • Tissue plasminogen activator (tPA)
    • Recombinant plasminogen activators (rtPA): tPAs that are produced by recombinant biotechnology techniques
      • Alteplase
      • Reteplase (rPA)
      • Tenecteplase (TNK-tPA)
  • Non-fibrin-specific agents
    • Streptokinase: enzyme produced by group A streptococci; catalyzes the conversion of plasminogen to plasmin
    • Urokinase: serine protease found in plasma, urine, and various types of tissue that is also used in fibrinolytic therapy
• Mechanism of action: directly or indirectly increase the concentration of plasmin → cleavage of thrombin and fibrin ^[5]
• Laboratory findings
  • ↑ PT
  • ↑ PTT
  • Normal platelet count
• Adverse effects
  • Bleeding (e.g., intracranial hemorrhage)
  • Hypersensitivity reactions (esp. to streptokinase) ^[6]
• Indications
  • Early STEMI (< 12 hours)
  • Early ischemic stroke (< 3 hours)
  • Massive pulmonary embolism
• Contraindications to fibrinolytic therapy
  • Active bleeding
  • Prior intracranial hemorrhage
  • Recent surgery
  • Severe hypertension
  • Known bleeding diathesis
• Reversal of adverse effects
  • Antifibrinolytics: group of drugs that impair fibrinolysis, typically by interfering with plasmin formation
    • Tranexamic acid: a synthetic lysine analog and inhibitor of plasminogen with antifibrinolytic action
    • Aminocaproic acid: a lysine derivative and inhibitor of plasminogen activators and plasmin with antifibrinolytic action
  • Fresh frozen plasma (FFP), PCC, or cryoprecipitate (Cryoprecipitate is obtained from frozen blood plasma via centrifuge and contains more factor VIII and fibrinogen than FFP.)
  • Platelet transfusions (if necessary)

Alteplase is a synthetic tissue plasminogen activator that converts plasminogen to plasmin. It is used in the treatment of STEMI, massive pulmonary embolism, and ischemic stroke.

Hemorrhagic diathesis is the abnormally increased susceptibility to bleeding.

Disorders of primary hemostasis

• Platelet disorders ^[7]
  • Platelet deficiency (see “Etiology” in “Thrombocytopenia”)
  • Platelet dysfunction (thrombocytopathy): disorders that lead to dysfunctional adhesion or aggregation of platelets
    • Inherited
      • Von Willebrand disease
      • Bernard-Soulier syndrome
      • Glanzmann thrombasthenia
    • Acquired
      • Drug-induced: e.g., aspirin, NSAID, clopidogrel
      • Immune thrombocytopenic purpura
      • Chronic kidney disease
      • Cardiopulmonary bypass ^[8]
    • See also ”Differential diagnosis of platelet disorders.”
• Disorders affecting the vessel wall
  • Vascular hemorrhagic diathesis (e.g., IgA vasculitis, hereditary hemorrhagic telangiectasia)
  • Thrombotic microangiopathy (e.g., HUS and TTP)
  • Conditions with impaired collagen synthesis (e.g., scurvy, Ehlers-Danlos syndrome)

Disorders of secondary hemostasis (disorders of the coagulation cascade)

• Intrinsic pathway
  • Factor VIII deficiency (hemophilia A)
  • Factor IX deficiency (hemophilia B)
  • Factor XI deficiency (hemophilia C)
• Extrinsic pathway: factor VII deficiency (autosomal recessive bleeding disorder caused by mutation of the F7 gene)
• Both pathways
  • Deficiency or inhibition of vitamin K-dependent coagulation factors II, VII, IX, and X
    • Vitamin K deficiency: e.g., malabsorption syndrome, depletion of gut flora (e.g., following antibiotic administration), vitamin K deficiency bleeding of the newborn
    • Vitamin K antagonist therapy (e.g., warfarin)
  • Inhibition of coagulation factors by autoantibodies (most commonly anti-factor VIII) ^[9]
  • Disseminated intravascular coagulation (DIC)
  • Impaired hepatic production of coagulation factors (e.g., cirrhosis)
  • Fibrinogen deficiency
  • Anticoagulant treatment

In disorders of primary hemostasis, platelet aggregation is impaired, whereas in disorders of secondary hemostasis it is the coagulation cascade that is impaired.

Hyperfibrinolysis ^[10]

• Definition: pathological fibrinolysis, which leads to bleeding
• Etiology
  • Disseminated intravascular coagulation (secondary to liver dysfunction, sepsis, etc.)
  • Peripartum complications
  • Treatment with fibrinolytics
  • Surgery in tPA-rich organs such as the prostate and uterus
  • Prostate carcinoma (paraneoplastic)
• Pathophysiology: excessive plasmin activity → increased fibrin degradation → thrombus instability and dissolution shortly after formation

• A thorough physical examination is essential for diagnosing bleeding disorders and should include the inspection of the entire skin, mucosa (esp. oral cavity), and joints.
• Watch out for signs of physical abuse, which may produce patterns of bruising that resemble those of bleeding disorders. Signs of physical abuse include:
  • Inconsistency of clinical findings and history
  • Atypical bruising patterns (e.g., on back, forehead, ears, neck) and/or retinal hemorrhages in children ≤ 4 years (see “Battered child syndrome”)

Superficial, petechial bleeding indicates defects of primary hemostasis, whereas large, palpable ecchymoses and deep tissue bleeding suggest defects of secondary hemostasis!

Clinical assessment and basic laboratory testing are used to differentiate between primary and secondary disorders of hemostasis. Advanced testing is used to identify the specific disorder.

Clinical assessment ^[13][14][15]

• Symptoms
  • Ask about features of mucosal, skin, and deep-tissue bleeding (see “Clinical features”).
  • Quantify bleeding severity with a bleeding assessment tool.
• Features associated with bleeding disorders
  • Known bleeding disorder in a family member
  • Chronic illness: e.g., chronic kidney disease, liver disease, malignancy, autoimmune diseases, malabsorption
  • Acute illness: e.g., recent infections , sepsis , use of mechanical circulatory support
  • Poor nutritional status
  • Pregnancy
• Use of medications
  • Antithrombotic agents: anticoagulants, antiplatelet agents
  • Other drugs that can affect platelet function and/or count, including:
    • Chemotherapeutic agents
    • NSAIDs
    • Phosphodiesterase inhibitors (e.g., cilostazol, sildenafil, theophylline)
    • Beta-lactam antibiotics
    • Antimycotis and antibiotics (e.g., miconazole, nitrofurantoin)
    • Nitrates
    • Antidepressants

Most bleeding disorders are acquired; i.e., secondary to medications or associated with acute or chronic illness. ^[13]

Women presenting with menorrhagia should also be evaluated by a gynecologist.

Initial laboratory studies ^{[14][15][16][23]}

• Indications
  • History or physical examination suggestive of a bleeding disorder
  • Elevated BAT score
• Studies
  • CBC, BMP, liver chemistries
  • Peripheral blood smear
    • Platelet clumping: suggests pseudothrombocytopenia
    • Schistocytes or other fragmented cells: consistent with microangiopathic hemolytic anemia (e.g., thrombotic thrombocytopenic purpura)
    • Identification of blasts: suggests hematologic malignancies
  • Coagulation panel; including fibrinogen level: Elevated PT/INR and/or aPTT are suggestive of disorders of secondary hemostasis.
  • Platelet function analysis (PFA): Abnormal platelet function (or, if not available, a prolonged bleeding time; ) suggests a disorder of primary hemostasis. ^[15]
  • vWF antigen and vWF activity (vWF ristocetin activity): for diagnosis of vWD

Von Willebrand disease is the most common inherited bleeding disorder, affecting up to 1% of the population. Von Willebrand factor concentration and vWF activity are now commonly part of initial diagnostic studies. ^[16][23]

DIC is characterized by thrombosis, hemorrhage, and organ dysfunction and can be a medical emergency that requires immediate treatment.

A detailed clinical assessment and initial laboratory studies are sufficient to diagnose the most common disorders of hemostasis (e.g., platelet dysfunction secondary to medications or bleeding disorders associated with acute or chronic disease).

Treatment should be guided by a specialist and target the specific cause of the bleeding. Occasionally, the transfusion of blood products may be indicated. For patients with acute or major bleeding, see “Management of acute bleeding” below.

Disorders of primary hemostasis ^[29][30]

• Platelet transfusion
  • Used in the treatment of both thrombocytopenia and platelet dysfunction
  • Indications
    • Active bleeding
    • Prevention of bleeding during invasive procedures
    • Prophylactically in patients with extremely low platelet count ^[26]
• Disease-specific treatment
  • Uremic platelet dysfunction ^[31]
    • Preventative measures include dialysis, erythropoietin, and conjugated estrogens. ^[32]
    • Desmopressin: may be used prior to invasive procedures or to treat active bleeding
  • Drug-related platelet dysfunction ^[29]
    • Discontinue medications causing dysfunction.
    • Consider desmopressin
  • Immune thrombocytopenia: Treatment may include corticosteroids and IVIG. Platelet transfusion is typically ineffectual.
  • Heparin-induced thrombocytopenia: Stop all heparin and initiate an alternative form of anticoagulation.
  • HELLP syndrome: Consult obstetrician immediately for specific management.

One random donor platelet unit typically increases platelet count by 5,000–10,000/mm³ in a 70-kg patient. One apheresis unit (the equivalent of 6–8 single units) increases platelet count by 30,000–40,000/mm³. ^[33]

Disorders of secondary hemostasis

Inherited coagulation factor deficiency ^[23]

• Depending on the etiology, treatment can include one or more of the following:
  • Blood product transfusions
  • Replacement of specific coagulation factors, e.g.:
    • Factors VIII, IX, or XI (e.g., for hemophilia)
    • Concentrates containing vWF and factor VIII (for vWD)
  • Pharmacological therapy (e.g., desmopressin, antifibrinolytics)
  • Intravenous immunoglobulin therapy
  • Monoclonal antibody therapy
• See “Treatment” in “Hemophilia” and in “Von Willebrand Disease” for specific recommendations.

Acquired coagulation factor deficiency

• Vitamin K deficiency ^[34]
  • Dietary deficiency
    • Vitamin K replacement: phytonadione
    • Optimize enteral or parenteral nutrition.
  • Associated with anticoagulant use: See “Anticoagulant reversal” for specific recommendations.
• Liver disease: complex management ^[35][36][37]
  • Consult gastroenterology and hematology early.
  • Consider vitamin K replacement for patients with abnormal coagulation studies. ^[36][38]
  • Screen for and manage comorbid conditions that affect hemostasis (e.g., uremia, bacterial overgrowth, portal hypertension, thrombocytopenia).

The effect of liver disease on hemostasis is complex: The clinical effects of thrombocytopenia and reduced coagulation factor synthesis are often negated by a simultaneous decrease in the production of profibrinolytic factors. Bleeding often does not occur, even if the laboratory values of hemostasis are markedly abnormal. ^[35]

Management ^[13]

• Start ABCDE approach and stabilize the patient as needed.
• Establish appropriate IV access.
• Consult hematology service.
• Assess the need for anticoagulant reversal, discontinue ongoing anticoagulants and platelet inhibitors, unless contraindicated.
• Consider consultation for a procedural intervention to control bleeding (e.g., upper endoscopy, colonoscopy, surgery).
• Start transfusion of blood products if needed.
  • pRBCs: Target Hb using a liberal or restrictive transfusion strategy.
  • Platelet transfusion: for thrombocytopenia or as part of a massive transfusion protocol
  • Fresh frozen plasma (FFP), cryoprecipitate : as part of massive transfusion protocol or to replace coagulation factors and/or fibrinogen
  • Prothrombin complex concentrate: Use only with expert guidance; potentially fatal thrombotic complications may occur. ^[40][41]
• Consider replacement of specific coagulation factors
  • Known hemophilia: factors VIII, IX, or XI
  • Known von Willebrand disease (vWD): concentrates containing vWF and factor VIII
• Consider adjuvant drug therapy depending on suspected etiology
  • Anticoagulant reversal, e.g., Vitamin K (phytonadione ) ^[34]
  • Desmopressin ^[42]
  • Antifibrinolytics (e.g., for hyperfibrinolysis)

Diagnostics should not delay factor replacement therapy in patients with known bleeding disorders presenting with major bleeding. ^[43][44][45]

Patients with a suspected disorder of secondary hemostasis presenting with major bleeding can benefit from the transfusion of fresh frozen plasma while diagnostic studies are performed. ^[13]

Diagnostics ^[13]

• Routine testing
  • CBC with blood smear, BMP, liver chemistries, and type and cross
  • Coagulation studies: Obtain a coagulation panel and measure vWF and vWF activity.
• Viscoelastic hemostatic assays (VHAs): a point-of-care test with rapid results that provides a comprehensive assessment of hemostatic function ^[46][47][48]
  • Common modalities: thromboelastogram (TEG®), rotational thromboelastometry (ROTEM®), and Sonoclot®
  • Uses ^{[48][49][50][51][52]}
    • Rapid bleeding (e.g., cardiac and liver transplant surgery, trauma, DIC, peripartum hemorrhage)
    • Complex hemostasis disorders (e.g., liver disease)

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